Compounds for the treatment of metabolic disorders

ABSTRACT

Compounds useful for the treatment of various metabolic disorders, such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, cachexia, obesity, atherosclerosis and arteriosclerosis, are disclosed.

CROSS-REFERENCE TO PRIOR APPLICATIONS

[0001] This is a divisional of U.S. patent application Ser. No.10/167,839, filed Jun. 12, 2002, the content of which is incorporatedherein by reference. This application claims the benefit of U.S.Provisional Patent Application No. 60/297,282, filed Jun. 12, 2001, thecontent of which is incorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] Diabetes mellitus is a major cause of morbidity and mortality.Chronically elevated blood glucose leads to debilitating complications:nephropathy, often necessitating dialysis or renal transplant;peripheral neuropathy; retinopathy leading to blindness; ulceration ofthe legs and feet, leading to amputation; fatty liver disease, sometimesprogressing to cirrhosis; and vulnerability to coronary artery diseaseand myocardial infarction.

[0003] There are two primary types of diabetes. Type I, orinsulin-dependent diabetes mellitus (IDDM) is due to autoimmunedestruction of insulin-producing beta cells in the pancreatic islets.The onset of this disease is usually in childhood or adolescence.Treatment consists primarily of multiple daily injections of insulin,combined with frequent testing of blood glucose levels to guideadjustment of insulin doses, because excess insulin can causehypoglycemia and consequent impairment of brain and other functions.

[0004] Type II, or noninsulin-dependent diabetes mellitus (NIDDM)typically develops in adulthood. NIDDM is associated with resistance ofglucose-utilizing tissues like adipose tissue, muscle, and liver, to theactions of insulin. Initially, the pancreatic islet beta cellscompensate by secreting excess insulin. Eventual islet failure resultsin decompensation and chronic hyperglycemia. Conversely, moderate isletinsufficiency can precede or coincide with peripheral insulinresistance. There are several classes of drugs that are useful fortreatment of NIDDM: 1) insulin releasers, which directly stimulateinsulin release, carrying the risk of hypoglycemia; 2) prandial insulinreleasers, which potentiate glucose-induced insulin secretion, and mustbe taken before each meal; 3) biguanides, including metformin, whichattenuate hepatic gluconeogenesis (which is paradoxically elevated indiabetes); 4) insulin sensitizers, for example the thiazolidinedionederivatives rosiglitazone and pioglitazone, which improve peripheralresponsiveness to insulin, but which have side effects like weight gain,edema, and occasional liver toxicity; 5) insulin injections, which areoften necessary in the later stages of NIDDM when the islets have failedunder chronic hyperstimulation.

[0005] Insulin resistance can also occur without marked hyperglycemia,and is generally associated with atherosclerosis, obesity,hyperlipidemia, and essential hypertension. This cluster ofabnormalities constitutes the “metabolic syndrome” or “insulinresistance syndrome”. Insulin resistance is also associated with fattyliver, which can progress to chronic inflammation (NASH; “nonalcoholicsteatohepatitis”), fibrosis, and cirrhosis. Cumulatively, insulinresistance syndromes, including but not limited to diabetes, underliemany of the major causes of morbidity and death of people over age 40.

[0006] Despite the existence of such drugs, diabetes remains a major andgrowing public health problem. Late stage complications of diabetesconsume a large proportion of national health care resources. There is aneed for new orally active therapeutic agents which effectively addressthe primary-defects of insulin resistance and islet failure with feweror milder side effects than existing drugs.

[0007] Currently there are no safe and effective treatments for fattyliver disease. Therefore such a treatment would be of value in treatingthis condition.

SUMMARY OF THE INVENTION

[0008] This invention provides a biologically active agent, wherein theagent is a compound of the formula:

[0009] wherein n is 1 or 2; m is 0 or 1; q is 0 or 1; tis 0 or 1; R⁵ isalkyl having from 1 to 3 carbon atoms; R⁹ is hydrogen, halo, or alkoxyhaving from 1 to 3 carbon atoms;

[0010] A is phenyl, unsubstituted or substituted by 1 or 2 groupsselected from: halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl,alkoxy having 1 or 2 carbon atoms, and perfluoromethoxy; or cycloalkylhaving from 3 to 6 ring carbon atoms wherein the cycloalkyl isunsubstituted or one or two ring carbons are independentlymono-substituted by methyl or ethyl; or a 5 or 6 membered heteroaromaticring having 1 or 2 ring heteroatoms selected from N, S and O and theheteroaromatic ring is covalently bound to the remainder of the compoundof formula I by a ring carbon; and X is —CH₂—, Q is —OR¹ and R¹ isethyl; or X is —CH₂CR¹²R¹³— or —CH₂CH(NHAc)— wherein each of R¹² and R¹³is independently hydrogen or methyl, Q is OR¹ and R¹ is hydrogen oralkyl having from 1 to 7 carbon atoms; or X is —CH₂CH₂— and Q is NR¹⁰R¹¹wherein one of R¹⁰ and R¹¹ is hydrogen, alkyl having from 1 to 3 carbonatoms or hydroxy, and the other is hydrogen or alkyl having from 1 to 3carbon atoms; or when R¹ is hydrogen, a pharmaceutically acceptable saltof the compound.

[0011] This invention provides a biologically active agent, wherein theagent is a compound of the formula:

[0012] wherein n is 1 or 2; t is 0 or 1; m is 0 and r is 1, or m is 1and r is 0; A is phenyl, unsubstituted or substituted by 1 or 2 groupsselected from: halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl,alkoxy having 1 or 2 carbon atoms, and perfluoromethoxy; or cycloalkylhaving from 3 to 6 ring carbon atoms wherein the cycloalkyl isunsubstituted or one or two ring carbons are mono-substituted by methylor ethyl; or a 5 or 6 membered heteroaromatic ring having 1 or 2 ringheteroatoms selected from N, S and O and the heteroaromatic ring iscovalently bound to the remainder of the compound of formula II by aring carbon; Z is

[0013] R¹ is hydrogen or alkyl having from 1 to 7 carbon atoms; R⁴ ishydrogen; —NHCOOC(CH₃)₃; —NHCH₃; or —NHCH₂CH₃; or when R¹ is hydrogen, apharmaceutically acceptable salt of the compound.

[0014] This invention provides a biologically active agent, wherein theagent is a compound of the formula:

[0015] wherein

[0016] n is 1 or 2; A is phenyl, unsubstituted or substituted by 1 or 2groups selected from: halo, alkyl having 1 or 2 carbon atoms,perfluoromethyl, alkoxy having 1 or 2 carbon atoms, andperfluoromethoxy; or cycloalkyl having from 3 to 6 ring carbon atomswherein one or both ring carbons are independently mono-substituted bymethyl or ethyl; or a 5 or 6 membered heteroaromatic ring having 1 or 2ring heteroatoms selected from N, S and O and the heteroaromatic ring iscovalently bound to the remainder of the compound of formula III by aring carbon.

[0017] This invention provides a biologically active agent, wherein theagent is a compound of the formula:

[0018] wherein R¹ is hydrogen or alkyl having from 1 to 7 carbon atoms;or when R¹ is hydrogen, a pharmaceutically acceptable salt of thecompound.

[0019] This invention provides a biologically active agent, wherein theagent is a compound of the formula:

[0020] wherein n is 1 or 2; R¹ is hydrogen or alkyl having from 1 to 7carbon atoms; R¹⁴ is hydroxy or hydrogen; and A is phenyl, unsubstitutedor substituted by 1 or 2 groups selected from halo, alkyl having 1 or 2carbon atoms, perfluoromethyl, alkoxy having 1 or 2 carbon atoms, andperfluoromethoxy; or cycloalkyl having from 3 to 6 ring carbon atomswherein the cycloalkyl is unsubstituted or one or two ring carbons areindependently mono-substituted by methyl or ethyl; or a 5 or 6 memberedheteroaromatic ring having 1 or 2 ring heteroatoms selected from N, Sand O and the heteroaromatic ring is covalently bound to the remainderof the compound of formula I by a ring carbon;

[0021] or a pharmaceutically acceptable salt of the compound.

[0022] This invention provides a biologically active agent, wherein theagent is a compound of the formula:

[0023] wherein n is 1 or 2; R¹ is hydrogen or alkyl having from 1 to 3carbon atoms; and A is phenyl, unsubstituted or substituted by 1 or 2groups selected from halo, alkyl having 1 or 2 carbon atoms,perfluoromethyl, alkoxy having 1 or 2 carbon atoms, andperfluoromethoxy; or cycloalkyl having from 3 to 6 ring carbon atomswherein the cycloalkyl is unsubstituted or one or two ring carbons areindependently mono-substituted by methyl or ethyl; or a 5 or 6 memberedheteroaromatic ring having 1 or 2 ring heteroatoms selected from N, Sand O and the heteroaromatic ring is covalently bound to the remainderof the compound of formula I by a ring carbon; or a pharmaceuticallyacceptable salt of the compound.

[0024] This invention provides a biologically active agent, wherein theagent is a compound of the formula:

[0025] wherein n is 1 or 2; R¹ is hydrogen or alkyl having from 1 to 3carbon atoms; and A is phenyl, unsubstituted or substituted by 1 or 2groups selected from halo, alkyl having 1 or 2 carbon atoms,perfluoromethyl, alkoxy having 1 or 2 carbon atoms, andperfluoromethoxy; or cycloalkyl having from 3 to 6 ring carbon atomswherein the cycloalkyl is unsubstituted or one or two ring carbons areindependently mono-substituted by methyl or ethyl; or a 5 or 6 memberedheteroaromatic ring having 1 or 2 ring heteroatoms selected from N, Sand O and the heteroaromatic ring is covalently bound to the remainderof the compound of formula I by a ring carbon; or a pharmaceuticallyacceptable salt of the compound.

[0026] This invention provides a biologically active agent, wherein theagent is a compound of the formula:

[0027] wherein n is 0, 1 or 2; R¹ is hydrogen or alkyl having from 1 to3 carbon atoms; R¹⁵ is hydrogen or alkyl having from 1 to 3 carbonatoms; R⁹ is hydrogen, halo, hydroxy, or alkoxy having from 1 to 3carbon atoms; A is phenyl, unsubstituted or substituted by 1 or 2 groupsselected from halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl,alkoxy having 1 or 2 carbon atoms, and perfluoromethoxy; or cycloalkylhaving from 3 to 6 ring carbon atoms wherein the cycloalkyl isunsubstituted or one or two ring carbons are independentlymono-substituted by methyl or ethyl; or a 5 or 6 membered heteroaromaticring having 1 or 2 ring heteroatoms selected from N, S and O and theheteroaromatic ring is covalently bound to the remainder of the compoundof formula I by a ring carbon; or a pharmaceutically acceptable salt ofthe compound.

[0028] The biologically active agents described above have activity inone or more of the biological activity assays described below, which areestablished animal models of human diabetes and insulin resistancesyndrome. Therefore such agents would be useful in the treatment ofdiabetes and insulin resistance syndrome. All of the exemplifiedcompounds that were tested demonstrated activity in the biologicalactivity assay or assays in which they were tested.

[0029] This invention provides the use of the biologically active agentsdescribed above in the manufacture of a medicament for the treatment ofinsulin resistance syndrome, diabetes, cachexia, hyperlipidemia, fattyliver disease, obesity, atherosclerosis or arteriosclerosis. Thisinvention also provides methods of treating a mammalian subject withinsulin resistance syndrome, diabetes, cachexia, hyperlipidemia, fattyliver disease, obesity, atherosclerosis or arteriosclerosis comprisingadministering to the subject an effective amount of a biologicallyactive agent in accordance with this invention. This invention alsoprovides a pharmaceutical composition comprising a biologically activeagent of this invention and a pharmaceutically acceptable carrier.

[0030] This invention provides certain novel intermediates, which areuseful in producing the biologically active agents of this invention.The invention also provides processes of producing the biologicallyactive agents and intermediates.

BRIEF DESCRIPTION OF THE FIGURES

[0031]FIG. 1: Serum insulin levels in high fat-fed C57B1/6J micereceiving vehicle (negative control), Compound BI, Compound BL, Wy14643or rosiglitazone.

[0032]FIG. 2: Serum leptin levels in high fat-fed C57B1/6J micereceiving vehicle (negative control), Compound BI, Compound BL, Wy14643or rosiglitazone.

DETAILED DESCRIPTION OF THE INVENTION

[0033] Definitions

[0034] As used herein the term “alkyl” means a linear or branched-chainalkyl group. An alkyl group identified as having a certain number ofcarbon atoms means any alkyl group having the specified number ofcarbons. For example, an alkyl having three carbon atoms can be propylor isopropyl; and alkyl having four carbon atoms can be n-butyl,1-methylpropyl, 2-methylpropyl or t-butyl.

[0035] As used herein the term “halo” refers to one or more of fluoro,chloro, bromo, and iodo.

[0036] As used herein the term “perfluoro” as in perfluoromethyl orperfluoromethoxy, means that the group in question has fluorine atoms inplace of all of the hydrogen atoms.

[0037] As used herein “Ac” refers to the group CH₃C(O)—.

[0038] Examples of the biologically active compounds of the instantinvention are listed below. These compounds are referred to herein bytheir chemical name or by the two-letter code shown below.

[0039] AA 4-(4-(2-Fluorobenzyloxy)phenyl)-4-oxobutyric acid;

[0040] AB 4-(4-(2-Methoxybenzyloxy)phenyl)-4-oxobutyric acid;

[0041] AC 3-[(4-(2-Fluorobenzyloxy)phenyl)-methylthio]propionic acid;

[0042] AD 4-(4-(3-Fluorobenzyloxy)phenyl)-4-oxobutyric acid;

[0043] AE 4-(4-(4-Fluorobenzyloxy)phenyl)-4-oxobutyric acid;

[0044] AF 4-(4-((2-Pyridinyl)-methoxy)phenyl)-4-oxobutyric acid;

[0045] AG 4-(4-(Benzyloxy)phenyl)-4-oxobutyric acid;

[0046] AH 4-(4-(2,6-Difluorobenzyloxy)phenyl)-4-oxobutyric acid;

[0047] AI 4-(4-(2-Chlorobenzyloxy)phenyl)-4-oxobutyric acid;

[0048] AJ 4-(4-(2-(2-Fluorophenyl)ethoxy)phenyl)-4-oxobutyric acid;

[0049] AK Ethyl 4-(4-(2-fluorobenzyloxyl)phenyl)-4-oxobutyrate;

[0050] AL 4-(4-(2-Methylbenzyloxy)phenyl)-4-oxobutyric acid;

[0051] AM4-[4-(2-(N-(2-fluorobenzyl)-N-methylamino)ethoxy)phenyl]-4-oxobutyricacid;

[0052] AN 4-(3-(2-Methylbenzyloxy)phenyl)-4-oxobutyric acid;

[0053] AO Ethyl 4-(3-(2-fluorobenzyloxyl)phenyl)-4-oxobutyrate;

[0054] AP Ethyl 4-(4-(2-methylbenzyloxyl)phenyl)-4-oxobutyrate;

[0055] AQ Ethyl 4-(4-(2,6-difluorobenzyloxyl)phenyl)-4-oxobutyrate;

[0056] AR 4-(4-(2-(2-Thienyl)ethoxy)phenyl)-4-oxobutyric acid;

[0057] AS 4-(2,6-Difluorophenyl)-4-oxobutyric acid;

[0058] AT 4-(4-(2,5-Dimethylbenzyloxy)phenyl)-4-oxobutyric acid;

[0059] AU 4-(4-(2,5-Difluorobenzyloxy)phenyl)-4-oxobutyric acid;

[0060] AV 4-(4-(2,4-Difluorobenzyloxy)phenyl)-4-oxobutyric acid;

[0061] AW 4-(3-(2,6-Difluorobenzyloxy)phenyl)-4-oxobutyric acid;

[0062] AX 4-(4-((Cyclopropyl)-methoxy)phenyl)-4-oxobutyric acid;

[0063] AY 4-(4-(2-Trifluoromethylbenzyloxy)phenyl)-4-oxobutyric acid;

[0064] AZ 3-[(4-(2,6-Difluorobenzyloxy)phenyl)-methylthio]propionicacid;

[0065] BA 4-(2-(2,6-Difluorobenzyloxy)phenyl)-4-oxobutyric acid;

[0066] BB Ethyl 4-(4-(2,6-difluorobenzyloxy)phenyl)-3-oxobutyrate;

[0067] BC3-(2-(4-(2,6-Difluorobenzyloxy)phenyl)-2-oxoethyl)thio-1H-1,2,4-triazole;

[0068] BD 5-[(4-(2,6-Difluorobenzyloxy)phenyl)-methyl]-1H-tetrazole;

[0069] BE(2RS)2-(N-Boc)-3-[2-(4-(2,6-difluorobenzyloxy)phenyl)-2-oxoethyl]thiopropionicacid;

[0070] BF Ethyl 2-Hydroxy-4-oxo-4-(4-(2,6-difluorobenzyloxy)phenyl)but-2-enoate;

[0071] BG(2RS)2-(N-Acetyl)-4-(4-(2,6-difluorobenzyloxy)phenyl)-4-oxobutyric acid;

[0072] BH 4-(3-((Cyclopropyl)-methoxy)phenyl)-4-oxobutyric acid;

[0073] BI 4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutyric acid;

[0074] BJ 4-(3-(2-Fluoro-6-methylbenzyloxy)phenyl)-4-oxobutyric acid;

[0075] BK Ethyl 4-(3-(2,6-dimethylbenzyloxyl)phenyl)-4-oxobutyrate;

[0076] BL 4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutyric acid Sodiumsalt;

[0077] BM 4-(4-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutyric acid;

[0078] BN 4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutyric acidPotassium salt;

[0079] BO 4-(3-(2,6-Dimethoxybenzyloxy)phenyl)-4-oxobutyric acid;

[0080] BP 4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxo-2,2-dimethylbutyricacid;

[0081] BQ 4-(3-(4-Trifluoromethylbenzyloxy)phenyl)-4-oxobutyric acid;

[0082] BR 4-(3-((Cyclobutyl)-methoxy)phenyl)-4-oxobutyric acid;

[0083] BS 4-(3-(2,6-Dimethylbenzyloxy)phenyl)butyric acid;

[0084] BT 4-[[4-(2,6-Dimethylbenzyloxy)-3-methoxy]phenyl]-4-oxobutyricacid;

[0085] BU4-{3-[((4-Trifluoromethylbenzylamino)-carbonyl)-4-methoxy]phenyl}-4-oxobutyricacid;

[0086] BV4-{3-[((2,6-Dimethyllbenzylamino)-carbonyl)-4-methoxy]phenyl}-4-oxobutyricacid;

[0087] BW 4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutanecarbohydroxamicacid;

[0088] BX 4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutyramide;

[0089] BY 4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxo-2-butenoic acid; and

[0090] BZ 4-(3-(2,6-Dimethylbenzyloxy)phenyl)-3-butenoic acid.

[0091] As used herein the transitional term “comprising” is open-ended.A claim utilizing this term can contain elements in addition to thoserecited in such claim.

DETAILED DESCRIPTION OF ACTIVE COMPOUNDS

[0092] In an embodiment of the agent of Formula I′, the agent is acompound of the formula:

[0093] wherein n is 1 or 2; m is 0 or 1; q is 0 or 1, t is 0 or 1; R⁵ isalkyl having from 1 to 3 carbon atoms; A is phenyl, unsubstituted orsubstituted by 1 or 2 groups selected from: halo, alkyl having 1 or 2carbon atoms, perfluoromethyl, alkoxy having 1 or 2 carbon atoms, andperfluoromethoxy; or cycloalkyl having from 3 to 6 ring carbon atomswherein the cycloalkyl is unsubstituted or one or two ring carbons areindependently mono-substituted by methyl or ethyl; or a 5 or 6 memberedheteroaromatic ring having 1 or 2 ring heteroatoms selected from N, Sand O and the heteroaromatic ring is covalently bound to the remainderof the compound of formula I by a ring carbon; and X is —CH₂— and R¹ isethyl; or X is —CH₂CH₂— or —CH₂CH(NHAc)— and R¹ is hydrogen or alkylhaving from 1 to 7 carbon atoms; or when R¹ is hydrogen, apharmaceutically acceptable salt of the compound.

[0094] In different embodiments of the agent of Formula I, R¹ ishydrogen or ethyl; q is 0; or X is —CH₂CH₂—.

[0095] In another embodiment of the agent of Formula I, A is phenyl,unsubstituted or substituted by 1 or 2 groups selected from: halo, alkylhaving 1 or 2 carbon atoms, perfluoromethyl, alkoxy having 1 or 2 carbonatoms, and perfluoromethoxy each halo is independently fluoro or chloro.In a specific embodiment each halo substituent on phenyl ring A isfluoro. In a more specific embodiment phenyl ring A is substituted by 2fluoro groups. In a specific embodiment the alkyl, perluoroalkyl, alkoxyor perfluoroalkoxy has 1 carbon atom.

[0096] In another embodiment of the agent of Formula I, A is cycloalkylhaving from 3 to 6 ring carbon atoms wherein the cycloalkyl isunsubstituted or one or two ring carbons are independentlymono-substituted by methyl or ethyl. In a specific embodiment thecycloalkyl is unsubstituted or one or both ring carbons adjacent to thering carbon covalently bound to the remainder of the compound of formulaI are independently mono-substituted by methyl or ethyl. In a morespecific embodiment A is unsubstituted cyclopropyl.

[0097] In another embodiment of the agent of Formula I, q is 1 and R⁵ ismethyl.

[0098] In another embodiment the agent is a compound of the formula:

[0099] wherein n is 1 or 2; m is 0 or 1; q is or 1; t is 0 or 1; R² andR³ are each independently selected from hydrogen, halo, alkyl having 1or 2 carbon atoms, perfluoromethyl, alkoxy having 1 or 2 carbon atoms,and perfluoromethoxy; R⁵ is alkyl having from 1 to 3 carbon atoms; and Xis —CH₂— and R¹ is ethyl; or X is —CH₂CH₂— or —CH₂CH(NHAc)— and R¹ ishydrogen or alkyl having from 1 to 7 carbon atoms; or when R¹ ishydrogen, a pharmaceutically acceptable salt of the compound. In a morespecific embodiment R¹ is hydrogen or ethyl. Examples of compounds ofFormula IA include Compound AM and Compound BG.

[0100] In a specific embodiment the agent is a compound of the formula:

[0101] wherein n is 1 or 2; m is 0 or 1; p is 1 and R¹ is ethyl; or p is2 and R¹ is hydrogen or alkyl having from 1 to 7 carbon atoms; R² and R³are each independently selected from hydrogen, halo, alkyl having 1 or 2carbon atoms, perfluoromethyl, alkoxy having 1 or 2 carbon atoms, andperfluoromethoxy; or when R¹ is hydrogen, a pharmaceutically acceptablesalt of the compound. In a more specific embodiment R¹ is hydrogen orethyl. In a still more specific embodiment one of R² and R³ is hydrogenor halo and the other is halo. Examples of such compounds includeCompound AD, Compound AE and Compound AI. In another still more specificembodiment R² is fluoro and R³ is hydrogen. Examples of such compoundsinclude Compound AA, Compound AJ, Compound AK, and Compound AO. Inanother still more specific embodiment R² is fluoro and R³ is fluoro.Examples of such compounds include Compound AU, Compound AV and CompoundBB.

[0102] In a more specific embodiment the agent is a compound of theformula:

[0103] wherein n is 1 or 2; m is 0; R¹ is H or alkyl having from 1 to 7carbon atoms; or when R¹ is hydrogen, a pharmaceutically acceptable saltof the compound. Examples of such compounds include Compound AH,Compound AQ, Compound AW and Compound BA. In a still more specificembodiment one of R² and R³ is methyl, methoxy or perfluoromethyl andthe other is hydrogen or methyl. In one embodiment R² is methyl, methoxyor perfluoromethyl and R³ is hydrogen. Examples of such compoundsinclude Compound AB, Compound AL, Compound AN, Compound AP and CompoundAY. In another embodiment R² is methyl and R³ is methyl. Examples ofsuch compounds include Compound AT and Compound BI. In anotherembodiment R² is hydrogen and R³ is hydrogen. Examples of such compoundsinclude Compound AG.

[0104] In another embodiment the agent is a compound of the formula:

[0105] wherein R¹ is hydrogen or alkyl having from 1 to 7 carbon atoms,or when R¹ is hydrogen, a pharmaceutically acceptable salt of thecompound. In a specific embodiment R¹ is hydrogen or ethyl. Examples ofsuch compounds include Compound AX and Compound BH.

[0106] In another embodiment the agent is a compound of the formula:

[0107] wherein n is 1 or 2; R¹ is hydrogen or alkyl having from 1 to 7carbon atoms; and Het is a or 6 membered heteroaromatic ring having 1 or2 ring heteroatoms selected from N, S and O and the heteroaromatic ringis covalently bound to the remainder of the compound of formula IC by aring carbon. In a specific embodiment R¹ is hydrogen or ethyl. Examplesof such compounds include Compound AF and Compound AR.

[0108] In an embodiment of the agent of Formula II, A is cycloalkylhaving from 3 to 6 ring carbon atoms wherein the cycloalkyl isunsubstituted or one or both of the ring carbons adjacent to theremainder of the compound of formula II are mono-substituted by methylor ethyl. In another embodiment of the agent of Formula II, A is phenyl,unsubstituted or substituted by 1 or 2 groups selected from: fluoro,alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxy having 1 or 2carbon atoms, and perfluoromethoxy.

[0109] In another embodiment, the agent is a compound of the formula:

[0110] wherein m is 0 or 1; r is 0 or 1; Z is

[0111] R¹ is hydrogen or alkyl having from 1 to 7 carbon atoms; R⁴ ishydrogen; —NHCOOC(CH₃)₃; —NHCH₃; or —NHCH₂CH₃; R³ is hydrogen or halo;or when R¹ is hydrogen, a pharmaceutically acceptable salt of thecompound. In a specific embodiment R¹ is hydrogen or ethyl. Examples ofsuch compounds include Compound AC, Compound AZ, Compound BC andCompound BE.

[0112] In an embodiment of the agent of Formula III, A is phenyl,unsubstituted or substituted by. 1 or 2 groups selected from: halo,alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxy having 1 or 2carbon atoms, and perfluoromethoxy. Examples of such compounds includeCompound BD.

[0113] In an embodiment of the agent of Formula IV, R¹ is hydrogen orethyl. Examples of such compounds include Compound AS.

[0114] In an embodiment of the agent of Formula V′, the agent is acompound of the formula:

[0115] wherein n is 1 or 2; R¹ is hydrogen or alkyl having from 1 to 7carbon atoms; A is phenyl, unsubstituted or substituted by 1 or 2 groupsselected from halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl,alkoxy having 1 or 2 carbon atoms, and perfluoromethoxy; or cycloalkylhaving from 3 to 6 ring carbon atoms wherein the cycloalkyl isunsubstituted or one or two ring carbons are independentlymono-substituted by methyl or ethyl; or a 5 or 6 membered heteroaromaticring having 1 or 2 ring heteroatoms selected from N, S and O and theheteroaromatic ring is covalently bound to the remainder of the compoundof formula I by a ring carbon; or a pharmaceutically acceptable salt ofthe compound.

[0116] In an embodiment of the agent of Formula V, the agent is acompound of the formula:

[0117] wherein n is 1 or 2; R¹ is hydrogen or alkyl having from 1 to 7carbon atoms; R² and R³ are each independently selected from hydrogen,halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxy having 1or 2 carbon atoms, and perfluoromethoxy, or a pharmaceuticallyacceptable salt of the compound. In a specific embodiment R¹ is hydrogenor ethyl. Examples of such compounds include Compound BF.

[0118] Use in Methods of Treatment

[0119] This invention provides a method for treating a mammalian subjectwith a condition selected from the group consisting of insulinresistance syndrome and diabetes (both primary essential diabetes suchas Type I Diabetes or Type II Diabetes and secondary nonessentialdiabetes), comprising administering to the subject an amount of abiologically active agent as described herein effective to treat thecondition. In accordance with the method of this invention a symptom ofdiabetes or the chance of developing a symptom of diabetes, such asatherosclerosis, obesity, hypertension, hyperlipidemia, fatty liverdisease, nephropathy, neuropathy, retinopathy, foot ulceration andcataracts, each such symptom being associated with diabetes, can bereduced. This invention also provides a method for treatinghyperlipidemia comprising administering to the subject an amount of abiologically active agent as described herein effective to treat thecondition. As shown in the Examples, compounds reduce serumtriglycerides and free fatty acids in hyperlipidemic animals. Thisinvention also provides a method for treating cachexia comprisingadministering to the subject an amount of a biologically active agent asdescribed herein effective to treat the cachexia. This invention alsoprovides a method for treating obesity comprising administering to thesubject an amount of a biologically active agent as described hereineffective to treat the condition. This invention also provides a methodfor treating a condition selected from atherosclerosis orarteriosclerosis comprising administering to the subject an amount of abiologically active agent as described herein effective to treat thecondition. The active agents of this invention are effective to treathyperlipidemia, fatty liver disease, cachexia, obesity, atherosclerosisor arteriosclerosis whether or not the subject has diabetes or insulinresistance syndrome. The agent can be administered by any conventionalroute of systemic administration. Preferably the agent is administeredorally. Other routes of administration that can be used in accordancewith this invention include rectally, parenterally, by injection (e.g.intravenous, subcutaneous, intramuscular or intraperitioneal injection),or nasally.

[0120] Further embodiments of each of the uses and methods of treatmentof this invention comprise administering any one of the embodiments ofthe biologically active agents described above. In the interest ofavoiding unnecessary redundancy, each such agent and group of agents isnot being repeated, but they are incorporated into this description ofuses and methods of treatment as if they were repeated.

[0121] Many of the diseases or disorders that are addressed by thecompounds of the invention fall into two broad categories: Insulinresistance syndromes and consequences of chronic hyperglycemia.Dysregulation of fuel metabolism, especially insulin resistance, whichcan occur in the absence of diabetes (persistent hyperglycemia) per se,is associated with a variety of symptoms, including hyperlipidemia,atherosclerosis, obesity, essential hypertension, fatty liver disease(NASH; nonalcoholic steatohepatitis), and, especially in the context ofcancer or systemic inflammatory disease, cachexia. Cachexia can alsooccur in the context of Type I Diabetes or late-stage Type II Diabetes.By improving tissue fuel metabolism, active agents of the invention areuseful for preventing or amelioriating diseases and symptoms associatedwith insulin resistance, as is demonstrated in animals in the Examples.While a cluster of signs and symptoms associated with insulin resistancemay coexist in an individual patient, it many cases only one symptom maydominate, due to individual differences in vulnerability of the manyphysiological systems affected by insulin resistance. Nonetheless, sinceinsulin resistance is a major contributor to many disease conditions,drugs which address this cellular and molecular defect are useful forprevention or amelioration of virtually any symptom in any organ systemthat may be due to, or exacerbated by, insulin resistance.

[0122] When insulin resistance and concurrent inadequate insulinproduction by pancreatic islets are sufficiently severe, chronichyperglycemia occurs, defining the onset of Type II diabetes mellitus(NIDDM). In addition to the metabolic disorders related to insulinresistance indicated above, disease symptoms secondary to hyperglycemiaalso occur in patients with NIDDM. These include nephropathy, peripheralneuropathy, retinopathy, microvascular disease, ulceration of theextremities, and consequences of nonenzymatic glycosylation of proteins,e.g. damage to collagen and other connective tissues. Attenuation ofhyperglycemia reduces the rate of onset and severity of theseconsequences of diabetes. Because, as is demonstrated in the Examples,active agents and compositions of the invention help to reducehyperglycemia in diabetes, they are useful for prevention andamelioration of complications of chronic hyperglycemia.

[0123] Both human and non-human mammalian subjects can be treated inaccordance with the treatment method of this invention. The optimal doseof a particular active agent of the invention for a particular subjectcan be determined in the clinical setting by a skilled clinician. In thecase of oral administration to a human for treatment of disordersrelated to insulin resistance, diabetes, hyperlipidemia, fatty liverdisease, cachexia or obesity the agent is generally administered in adaily dose of from 1 mg to 400 mg, administered once or twice per day.For oral administration to a human the anticipated preferred daily doseof Compound AH is from 100 mg to 400 mg; of Compound AW is from 30 to300 mg; and of Compound BI is from 0.10 to 200 mg. In the case of oraladministration to a mouse the agent is generally administered in a dailydose from 0.1 to 300 mg of the agent per kilogram of body weight. Activeagents of the invention are used as monotherapy in diabetes or insulinresistance syndrome, or in combination with one or more other drugs withutility in these types of diseases, e.g. insulin releasing agents,prandial insulin releasers, biguanides, or insulin itself. Suchadditional drugs are administered in accord with standard clinicalpractice. In some cases, agents of the invention will improve theefficacy of other classes of drugs, permitting lower (and therefore lesstoxic) doses of such agents to be administered to patients withsatisfactory therapeutic results. Established safe and effective doseranges in humans for representative compounds are: metformin 500 to 2550mg/day; glyburide 1.25 to 20 mg/day; GLUCOVANCE (combined formulation ofmetformin and glyburide) 1.25 to 20 mg/day glyburide and 250 to 2000mg/day metformin; atorvastatin 10 to 80 mg/day; lovastatin 10 to 80mg/day; pravastatin 10 to 40 mg/day; and simvastatin 5-80 mg/day;clofibrate 2000 mg/day; gemfibrozil 1200 to 2400 mg/day, rosiglitazone 4to 8 mg/day; pioglitazone 15 to 45 mg/day; acarbose 75-300 mg/day;repaglinide 0.5 to 16 mg/day.

[0124] Type I Diabetes Mellitus: A patient with Type I diabetes managestheir disease primarily by self-administration of one to several dosesof insulin per day, with frequent monitoring blood glucose to permitappropriate adjustment of the dose and timing of insulin administration.Chronic hyperglycemia leads to complications such as nephropathy,neuropathy, retinopathy, foot ulceration, and early mortality;hypoglycemia due to excessive insulin dosing can cause cognitivedysfunction or unconsciousness. A patient with Type I diabetes istreated with 1 to 400 mg/day of an active agent of this invention, e.g.50 to 400 mg/day of Compound AH, in tablet or capsule form either as asingle or a divided dose. The anticipated effect will be a reduction inthe dose or frequency of administration of insulin required to maintainblood glucose in a satisfactory range, and a reduced incidence andseverity of hypoglycemic episodes. Clinical outcome is monitored bymeasurement of blood glucose and glycosylated hemoglobin (an index ofadequacy of glycemic control integrated over a period of severalmonths), as well as by reduced incidence and severity of typicalcomplications of diabetes. A biologically active agent of this inventioncan be administered in conjunction with islet transplantation to helpmaintain the anti-diabetic efficacy of the islet transplant.

[0125] Type II Diabetes Mellitus: A typical patient with Type IIdiabetes (NIDDM) manages their disease by programs of diet and exerciseas well as by taking medications such as metformin, glyburide,repaglinide, rosiglitazone, or acarbose, all of which provide someimprovement in glycemic control in some patients, but none of which arefree of side effects or eventual treatment failure due to diseaseprogression. Islet failure occurs over time in patients with NIDDM,necessitating insulin injections in a large fraction of patients. It isanticipated that daily treatment with an active agent of the invention(with or without additional classes of antidiabetic medication) willimprove glycemic control, reduce the rate of islet failure, and reducethe incidence and severity of typical symptoms of diabetes. In addition,active agents of the invention will reduce elevated serum triglyceridesand fatty acids, thereby reducing the risk of cardiovascular disease, amajor cause of death of diabetic patients. Suitable daily dose rangesfor selected compounds of the invention for treatment of NIDDM (eitheras monotherapy or in combination with other antidiabetic drugs) are from50 mg to 400 mg of Compound AH, from 15 mg to 300 mg of Compound AW, orfrom 5 mg to 200 mg of Compound BI. As is the case for all othertherapeutic agents for diabetes, dose optimization is done in individualpatients according to need, clinical effect, and susceptibility to sideeffects.

[0126] Hyperlipidemia: Elevated triglyceride and free fatty acid levelsin blood affect a substantial fraction of the population and are animportant risk factor for atherosclerosis and myocardial infarction.Active agents of the invention are useful for reducing circulatingtriglycerides and free fatty acids in hyperlipidemic patients. Suitabledaily dose ranges for selected compounds of the invention for treatmentof hypertriglyceridemia are from 50 mg to 400 mg of Compound AH, from 15mg to 300 mg of Compound AW, or from 5 mg to 200 mg of Compound BI.Hyperlipidemic patients often also have elevated blood cholesterollevels, which also increase the risk of cardiovascular disease.Cholesterol-lowering drugs such as HMG-CoA reductase inhibitors(“statins”) can be administered to hyperlipidemic patients in additionto agents of the invention, optionally incorporated into the samepharmaceutical composition.

[0127] Fatty Liver Disease: A substantial fraction of the population isaffected by fatty liver disease, also known as nonalcoholicsteatohepatitis (NASH); NASH is often associated with obesity anddiabetes. Hepatic steatosis, the presence of droplets of triglycerideswith hepatocytes, predisposes the liver to chronic inflammation(detected in biopsy samples as infiltration of inflammatory leukocytes),which can lead to fibrosis and cirrhosis. Fatty liver disease isgenerally detected by observation of elevated serum levels ofliver-specific enzymes such as the transaminases ALT and AST, whichserve as indices of hepatocyte injury, as well as by presentation ofsymptoms which include fatigue and pain in the region of the liver,though definitive diagnosis often requires a biopsy. As is shown in theExamples, compounds of the invention, e.g. Compound AW, reduce serumliver transaminases and liver fat content in an established animal modelof NASH (ob/ob obese mice), and are therefore useful for treatment offatty liver disease. An appropriate dose range of Compound AW fortreatment of fatty liver disease is 15 to 300 mg/day. The anticipatedbenefit is a reduction in liver inflammation and fat content, resultingin attenuation, halting, or reversal of the progression of NASH towardfibrosis and cirrhosis.

[0128] Pharmaceutical Compositions

[0129] This invention provides a pharmaceutical composition comprising abiologically active agent as described herein and a pharmaceuticallyacceptable carrier. Further embodiments of the pharmaceuticalcomposition of this invention comprise any one of the embodiments of thebiologically active agents described above. In the interest of avoidingunnecessary redundancy, each such agent and group of agents is not beingrepeated, but they are incorporated into this description ofpharmaceutical compositions as if they were repeated.

[0130] Preferably the composition is adapted for oral administration,e.g. in the form of a tablet, coated tablet, dragee, hard or softgelatin capsule, solution, emulsion or suspension. In general the oralcomposition will comprise from 1 mg to 400 mg of such agent. It isconvenient for the subject to swallow one or two tablets, coatedtablets, dragees, or gelatin capsules per day. Accordingly, preferredoral compositions for treatment of humans comprise from 50 mg to 400 mgof Compound AH, from 15 mg to 300 mg of Compound AW, or from 5 mg to 200mg of Compound BI. However the composition can also be adapted foradministration by any other conventional means of systemicadministration including rectally, e.g. in the form of suppositories,parenterally, e.g. in the form of injection solutions, or nasally.

[0131] The biologically active compounds can be processed withpharmaceutically inert, inorganic or organic carriers for the productionof pharmaceutical compositions. Lactose, corn starch or derivativesthereof, talc, stearic acid or its salts and the like can be used, forexample, as such carriers for tablets, coated tablets, dragees and hardgelatin capsules. Suitable carriers for soft gelatin capsules are, forexample, vegetable oils, waxes, fats, semi-solid and liquid polyols andthe like. Depending on the nature of the active ingredient no carriersare, however, usually required in the case of soft gelatin capsules,other than the soft gelatin itself. Suitable carriers for the productionof solutions and syrups are, for example, water, polyols, glycerol,vegetable oils and the like. Suitable carriers for suppositories are,for example, natural or hardened oils, waxes, fats, semil-liquid orliquid polyols and the like.

[0132] The pharmaceutical compositions can, moreover, containpreservatives, solubilizers, stabilizers, wetting agents, emulsifiers,sweeteners, colorants, flavorants, salts for varying the osmoticpressure, buffers, coating agents or antioxidants. They can also containstill other therapeutically valuable substances, particularlyantidiabetic or hypolipidemic agents that act through mechanisms otherthan those underlying the effects of the compounds of the invention.Agents which can advantageously be combined with compounds of theinvention in a single formulation include but are not limited tobiguanides such as metformin, insulin releasing agents such as thesulfonylurea insulin releaser glyburide and other sulfonylurea insulinreleasers, cholesterol-lowering drugs such as the “statin” HMG-CoAreductase inhibitors such as atrovastatin, lovastatin, pravastatin andsimvastatin, PPAR-alpha agonists such as clofibrate and gemfibrozil,PPAR-gamma agonists such as thiazolidinediones (e.g. rosiglitazone andpioglitazone, alpha-glucosidase inhibitors such as acarbose (whichinhibit starch digestion), and prandial insulin releasers such asrepaglinide. The amounts of complementary agents combined with compoundsof the invention in single formulations are in accord with the dosesused in standard clinical practice. Established safe and effective doseranges for certain representative compounds are set forth above.

[0133] Reaction Schemes

[0134] The biologically active compounds of the present invention can bemade in accordance with the following reaction schemes.

[0135] The compound of formula I′ where X is —CH₂CR¹²R¹³—, q and m are0, t is 0 or 1, and n is 1 or 2, R⁹ is hydrogen, halo, or alkoxy having1 to 3 carbon atoms, Q is OR¹ where R¹ is hydrogen or alkyl having from1 to 7 carbons, i.e. compounds of formula:

[0136] wherein A is as described above, and R¹ is hydrogen or alkylhaving from 1 to 7 carbon atoms, R¹² and R¹³ is independently hydrogenor methyl can be prepared from the compound of formula VI via thereaction scheme in Scheme 1.

[0137] In the reaction scheme of Scheme 1, A, t, n and R⁹ are as above.R⁶ is an alkyl group containing from 1 to 7 carbon atoms, R¹² and R¹³ isindependently hydrogen or methyl and Y is a leaving group.

[0138] The compound of formula VI is converted to the compound offormula VIII via reaction of step (a) using Mitsunobu condensation of VIwith VII using triphenylphosphine and diethyl azodicarboxylate. Any ofthe conditions conventionally used in Mitsunobu reactions can beutilized to carry out the reaction of step (a).

[0139] The compound of formula VIII can also be prepared by etherifyingor alkylating the compound of formula VI with a compound of formula IXas in reaction of step (b). In the compound of formula IX, Y can be anyconventional leaving group such as mesyloxy, tosyloxy or a halide. Anyconventional method of etherifying of a hydroxyl group through reactionwith a halide or leaving group can be utilized to carry out the reactionof step (b). The reaction of step (b) is preferred over step (a) ifcompund of formula IX is readily available.

[0140] The compound of formula VIII is converted to the compound offormula XI via reaction of step (c) by alkylating the compound offormula VIII with the compound of formula X. This reaction is carriedout utilizing a conventional base which converts acetophenone to 3-ketoester (i.e. gamma-keto ester). Any conventional base for this purposecan be utilized in the reaction of step (c). In carrying out thisreaction it is generally preferred to utilize alkali metal salts ofhexamethyldisilazane such as lithium bis(trimethylsilyl)amide as base.Generally this reaction is carried out in an inert solvent such astetrahydrofuran: 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone(5:1). Any of the conditions conventional in such alkylation reactionscan be utilized to carry out the reaction of step (c).

[0141] The compound of formula XI is the compound of formula I′ where R¹is an alkyl group containing from 1 to 7 carbon atoms. The compound offormula XI can be converted to the free acid i.e. the compound offormula I′ where R¹ is H by ester hydrolysis. Any conventional method ofester hydrolysis will produce the compound of formula I′ where R¹ is H.

[0142] The compound of general formula VII can be prepared by reducingthe corresponding acid of formula A-(CH₂)_(t+n)—CO₂H. The reaction iscarried out first by esterification of compound of formulaA-(CH₂)_(t+n)CO₂H with methyl iodide, followed by reduction utilizing aconventional base for example, lithium aluminium hydride or the like inan inert organic solvent for example, tetrahydrofuran or the like. Anyof the conditions conventional in such reduction reactions can beutilized to carry out this reaction.

[0143] The compound of formula VII where A is 2,6 Dimethyl phenyl can beprepared from the compound of formula XCI, via the reaction scheme inScheme 2.

[0144] In Scheme 2, the compound of formula XCI can be converted tocompound of formula VII by esterification with methyl iodide, followedby reduction with lithium aluminum hydride via reaction of step (r″).The reaction of step (r″) can be carried out utilizing a conventionalreducing agent. In carrying out this reaction it is generally preferredto utilize lithium aluminum hydride as the reducing agent. Any of theconditions conventional in reduction reactions can be utilized to carryout this reaction.

[0145] The compound of formula I where X is —CH₂—, q is 0, m is 1, t is0 or 1 and n is 1 or 2, i.e. compounds of the formula:

[0146] wherein A is as described above, R¹ is ethyl, and R⁹ is hydrogen,halo, or alkoxy having 1 to 3 carbon atoms can be prepared from thecompound of formula XII, wherein m is as above via the reaction schemein Scheme 3.

[0147] In Scheme 3, A is as above, Y is a leaving group such as halide,mesyloxy or tosyloxy. Y¹ is chloro.

[0148] In Scheme 3, the compound of formula XII is converted into theethyl ester of formula XIII using ethanol via reaction of step (d). Anyconventional method of converting acid to ethyl ester can be utilized tocarry out this reaction.

[0149] The compound of formula XIII can be converted to compound offormula XIV in the same manner as described in the connection withreaction of step (a) or (b) hereinbefore.

[0150] In the step of (f), the compound of formula XIV is hydrolyzed toproduce the compound of formula XV. Any conventional method of basichydrolysis to hydrolyze ester can be utilized to carry out thisreaction.

[0151] The compound of formula XV is converted to the acid chloride offormula XVI via reaction of step (g) by reaction with thionyl chloride.Any of the conventional methods of converting acid to acid halide can beutilized to carry out this reaction of step (g).

[0152] The compound of formula XVII is reacted with acid chloride offormula XVI to produce the compound of formula XVIII via reaction ofstep (h). Any conventional base can be utilized to carry out thisreaction with the preferred base being pyridine. The resulting acylatedMeldrum acids were not isolated, and instead after workup they wererefluxed in absolute ethanol to give the 2-ketoesters. Any conventionalconditions to carry out the reaction of step (h) can be utilized.

[0153] The compound of formula XVIII is the compound of formula I whereR¹ is ethyl.

[0154] The compound of formula I′ where q is 1, R⁵ is an alkyl grouphaving 1 to 3 carbon atoms where X is —CH₂CR¹²R¹³—, m is 0, t is 0 or 1and n is 1 or 2, i.e. compounds of the formula:

[0155] wherein A is as above, R¹ is hydrogen or alkyl having from 1 to 7carbon

[0156] atoms, and R¹² and R¹³ is independently hydrogen or methyl, R⁹ ishydrogen, halo, or alkoxy having 1 to 3 carbon atoms, Q is OR¹ where R¹is hydrogen or alkyl having from 1 to 7 carbons, can be prepared fromthe compound of formula XIX, wherein t and A are as above via thereaction scheme in Scheme 4.

[0157] In Scheme 4, t, n, A, R¹, R⁹, R¹², R¹³ and R⁵ are as above. R⁶ isan alkyl group having 1 to 7 carbon atoms. Y¹ is chloro.

[0158] In Scheme 4, the compound of formula XIX is mesylated to furnishthe compound of formula XX via reaction of step (i). Any conventionalconditions to carry out mesylation can be utilized. The compound offormula XX is then heated with the compound of formula XXI to producethe compound of formula XXII. Any of the conditions conventional toproduce amino alcohol can be utilized in reaction of step (j).

[0159] In the compound of formula XXII, alcohol is then displaced bychloro by treating the compound of formula XXII with thionyl chloride toproduce compound of formula XXIII via reaction of step (k). Anyconventional method to displace alcohol with halo can be utilized tocarry out this reaction.

[0160] The compound of formula XXIII is reacted with a compound offormula VI in the presence of base using dimethylformamide as solventvia reaction of step (l) to produce the corresponding compound offormula XXIV. The position of the substituents in the compound offormula VI will determine the position of the substituents in thecompound of formula XXIV. Any conventional method of etherification of ahydroxyl group in the presence of base (preferred base being potassiumcarbonate) with a halide can be utilized to carry out the reaction ofstep (l). The compound of formula XXIV is converted to the compound offormula XXV via reaction of step (m) by alkylating the compound offormula XXIV with the compound of formula X in the presence of alkalimetal silyl amide as base (eg. lithium hexamethyldisilane or sodiumhexamethyldisilane). This reaction is carried out in the same manner asdescribed in connection with reaction of step (c) of Scheme 1.

[0161] The compound of formula XXV is the compound of formula I′ whereR¹ is an alkyl group having 1 to 7 carbon atoms. The compound of formulaXXV can be converted to the free acid i.e. the compound of formula I′where R¹ is H by ester hydrolysis. Any conventional method of esterhydrolysis will produce the compound of formula I′ where R¹ is H.

[0162] The compound of formula I′ where X is —CH₂CH(NHAc),— m is 0, q is0, t is 0 or 1 and n is 1 or 2, i.e. compounds of the formula:

[0163] wherein A is as above, R¹ is hydrogen on alkyl having from 1 to 7carbon atoms, and R⁹ is hydrogen, halo, or alkoxy having 1 to 3 carbonatoms, Q is OR¹ where R¹ is hydrogen or alkyl having from 1 to 7 carbonscan be prepared from the compound of formula VIII, via the reactionscheme in Scheme 5.

[0164] In Scheme 5, t, n, A, R⁹ and R¹ are as above. R⁷ is an alkylgroup having 1 to 7 carbon atoms.

[0165] The compound of formula VIII is prepared in the same manner asdescribed hereinbefore in connection with reaction of step (a) or (b) inScheme 1.

[0166] The compound of formula VIII is converted to compound of formulaXXVI by selective bromination of the methyl ketone moiety via reactionof step (n) by treating the compound of formula VIII with CuBr₂. Anyselective bromination conditions to convert methyl ketone to1-bromoketone can be utilized to carry out the reaction of step (n).

[0167] The compound of formula XXVI can be converted to compound offormula XXVIII via reaction of step (o) by treating the compound offormula XXVI with the sodium salt of compound of formula XXVII inethanol. Any conventional conditions for this alkylation reaction can beutilized to carry out this reaction.

[0168] The compound of formula XXVIII is converted to compound offormula XXIX via reaction of step (p) by de-esterification employing 4equivalents of sodium hydroxide.

[0169] Initial mono de-esterification followed by slow hydrolysis of theremaining ethyl ester was observed. Removal of solvent and incubation ofthe residue in acetic acid produced the compound of formula XXIX.

[0170] The compound of formula XXIX is the compound of formula I′ whereR¹ is H.

[0171] The compound of formula XXIX can be converted to compound offormula XXXI where R⁷ is an alkyl chain having 1 to 7 carbon atoms byesterification of carboxylic acid with compound of formula XXX usingN,N-dicyclohexylcarbodiimide as dehydrating condensing agent. Anyconditions conventional for this reaction can be utilized to carry outthe reaction of step (q).

[0172] The compound of formula XXXI is the compound of formula I′ whereR¹ is an alkyl chain having 1 to 7 carbon atoms.

[0173] The compound of formula I where X is —CH₂—, q and m are 0, t is 0or 1 and n is 1 or 2, i.e. compounds of formula:

[0174] wherein t, n, and A are as described above, R⁹ is hydrogen, halo,or alkoxy having 1 to 3 carbon atoms and R¹ is ethyl can be preparedfrom the compound of formula LX, via the reaction scheme in Scheme 6.

[0175] In the reaction scheme of Scheme 6, A, t, R⁹ and n are as above,Y is a leaving group and Y¹ is chloro.

[0176] In Scheme 6, the compound of formula LX is converted to compoundof formula LXI in the same manner as described hereinbefore inconnection with the reaction of steps (a) or (b) in Scheme 1.

[0177] In the step of (q′), the compound of formula LXI is hydrolyzed toproduce the compound of formula LXII in the same manner as described inconnection with the reaction of step (f) in Scheme 3.

[0178] The compound of formula LXII is converted to compound of formulaLXIII via reaction of step (r′) in the same manner as described inconnection with reaction of step (g) in Scheme 3.

[0179] The compound of formula LXIV is first treated with 2 equivalentsof n-butyllithium at low temperature and then compound of formula LXIIIis added to produce compound of formula LXV (Weirenga, W.; Skulnick, H.I. J.O.C. 1979, 44, 310-311).

[0180] The compound of formula LXV is the compound of formula 1 where R¹is ethyl.

[0181] The compound of formula I where q is 1, R⁵ is an alkyl grouphaving 1 to 3 carbon atoms, where X is —CH₂—, m is 0, t is 0 or I and nis 1 or 2, i.e. compounds of formula:

[0182] wherein A is as described above, R⁹ is hydrogen, halo, or alkoxyhaving 1 to 3 carbon atoms and R¹ is ethyl can be prepared from thecompound of formula LX via the reaction scheme in Scheme 7.

[0183] In the reaction scheme of Scheme 7, A, t, R⁹ and n are as above,Y¹ is chloro. R⁵ is an alkyl group having from 1 to 3 carbon atoms.

[0184] In Scheme 7, the compound of formula LX is reacted with compoundof formula XXIII (prepared in the same manner as described in Scheme 4)to produce the compound of formula LXVI via reaction of step (t′). Thisrection is carried out in the same manner as described hereinbefore inthe connection with reaction of step (l) in Scheme 4.

[0185] In the step of (u′), the compound of formula LXVI is hydrolyzedto produce the compound of formula LXVII in the same manner as describedin the reaction of step (f) in Scheme 3.

[0186] The compound of formula LXVII is converted to compound of formulaLXVIII via reaction of step (v′) in the same manner as described inconnection with the reaction of step (g) in Scheme 3.

[0187] The compound of formula LXIV is first treated with 2 equiv ofn-butyllithium at low temperature and then compound of formula LXIII isadded to produce compound of formula LXV (Weirenga, W.; Skulnick, H. I.J.O.C. 1979, 44, 310-311).

[0188] The compound of formula LXIX is the compound of formula 1 whereR¹ is an alkyl group having 2 carbon atoms.

[0189] The compound of formula I′ where q is 1, R⁵ is an alkyl grouphaving 1 to 3 carbon atoms, R¹ is hydrogen or alkyl having from 1 to 7carbons, R⁹ is hydrogen, halo, or alkoxy having 1 to 3 carbon atoms, Qis OR¹ where R¹ is hydrogen or alkyl having from 1 to 7 carbons, X is—CH₂CH(NHAc)—, m is 0, t is 0 or 1 and n is 1 or 2, i.e. compounds ofthe formula:

[0190] wherein t, n, A and R¹ are as above, can be prepared from thecompound of formula VI, via the reaction scheme in Scheme 8.

[0191] In Scheme 8, t, n, A, R⁹ and R¹ are as above. R⁷ is an alkylgroup having 1 to 7 carbon atoms. R⁵ is an alkyl group having 1 to 3carbon atoms. Y¹ is chloro.

[0192] The compound of formula XXIV is prepared in the same manner asdescribed hereinbefore in connection with reaction of step (l) in Scheme4.

[0193] The compound of formula XXIV is converted to compound of formulaLXX by selective bromination of the methyl ketone moiety via reaction ofstep (x′) by treating the compound of formula XXIV with CuBr₂. Anyselective bromination conditions to convert methyl ketone to1-bromoketone can be utilized to carry out the reaction of step (x′).

[0194] The compound of formula LXX can be converted to the compound offormula LXXI via reaction of step (y′) by treating the compound offormula LXX with the sodium salt of compound of formula XXVII inethanol. Any conventional conditions can be utilized to carry outalkylation reaction.

[0195] The compound of formula LXXI is converted to the compound offormula LXXII via reaction of step (z′) by de-esterification employing 4equiv. of sodium hydroxide. This indicated an initial monode-esterification followed by slow hydrolysis of the remaining ethylester. Removal of solvent and incubation of the residue in acetic acidproduced the compound of formula LXXII.

[0196] The compound of formula LXXII is the compound of formula I′ whereR¹ is H.

[0197] The compound of formula LXXII can be converted to compound offormula LXXIII where R⁷ is an alkyl group having 1 to 7 carbon atoms byesterification of carboxylic acid with compound of formula XXX usingN,N-dicyclohexylcarbodiimide as dehydrating condensing agent. Anyconditions conventional for this reaction can be utilized to carry outthe reaction of step (a″).

[0198] The compound of formula LXXIII is the compound of formula I′where R¹ is an alkyl group having 1 to 7 carbon atoms.

[0199] The compound of formula I′ where X is —CH₂CH(NHAc)—, R⁹ ishydrogen, halo, or alkoxy having 1 to 3 carbon atoms, Q is OR¹ where R¹is hydrogen or alkyl having from 1 to 7 carbons, m is 1, q is 0, t is 0or 1 and n is 1 or 2, i.e. compounds of the formula:

[0200] wherein A is as above, and R¹ is hydrogen or alkyl having from 1to 7 carbon atoms can be prepared from the compound of formula LXXIV viathe reaction scheme in Scheme 9.

[0201] In Scheme 9, t, n, A, R 9 and R¹ are as above. R⁷ is an alkylgroup having 1 to 7 carbon atoms. R⁵ is an alkyl group having 1 to 3carbon atoms.

[0202] The compound of formula LXXIV can be prepared according to methoddescribed in Murphy et al J.C.S. Perkin 1, 1980, 1555-1566.

[0203] The compound of formula LXXIV can be alkylated to producecompound of formula LXXV via reaction of step (b″) employing eithercompound of formula VII using same method as described in the connectionof reaction step of (a) in Scheme 1 or compound of formula IX usingpotassium carbonate as the base for alkylation. The reaction is carriedout in the same manner as described hereinbefore in connection with thereaction of step (l) in Scheme 4.

[0204] The compound of formula LXXV is then selectively brominated at 0°C. using 30 wt % HBr in acetic acid dropwise to produce compound offormula LXXVI via reaction of step (c″). Any conventional method toconvert selectively substituted acetone to 1-Bromoacetone can beutilized to carry out this reaction of step (c″).

[0205] The compound of formula LXXVI is converted to compound of formulaLXXVII via reaction of step (d″) in the same manner as describedhereinbefore in connection with the reaction of step (o) in Scheme 5.

[0206] The compound of formula LXXVII is converted to compound offormula LXXVIII via reaction of step (e″) by de-esterification employing4 equiv. of sodium hydroxide. Initial mono de-esterification followed byslow hydrolysis of the remaining ethyl ester was observed. Removal ofsolvent and incubation of the residue in acetic acid produced thecompound of formula LXXVIII.

[0207] The compound of formula LXXVIII is the compound of formula I′where R¹ is H.

[0208] The compound of formula LXXVIII can be converted to compound offormula LXXIX where R⁷ is an alkyl group having 1 to 7 carbon atoms byesterification of carboxylic acid with compound of formula XXX usingN,N-dicyclohexylcarbodiimide as dehydrating condensing agent. Anyconditions conventional for this reaction can be utilized to carry outthe reaction of step (f″).

[0209] The compound of formula LXXIX is the compound of formula I′ whereR¹ is an alkyl group having 1 to 7 carbon atoms.

[0210] The compound of formula I′ where q is 1, R⁵ is an alkyl grouphaving 1 to 3 carbon atoms, X is —CH₂CH(NHAc)—, m is 1, t is 0 or 1 andn is 1 or 2, R⁹ is hydrogen, halo, or alkoxy having 1 to 3 carbon atoms,Q is OR¹ where R¹ is hydrogen or alkyl having from 1 to 7 carbons, i.e.compounds of the formula:

[0211] wherein A is as above, and R¹ is hydrogen or alkyl having from 1to 7 carbon atoms can be prepared from the compound of the formula LXXIVvia the reaction scheme in Scheme 10.

[0212] In Scheme 10, t, n, A, R⁹ and R¹ are as above. R⁷ is an alkylgroup having 1 to 7 carbon atoms. R⁵ is an alkyl group having 1 to 3carbon atoms. Y¹ is chloro.

[0213] The compound of formula LXXIV can be prepared according to methoddescribed in Murphy et. al. J.C.S. Perkin 1, 1980, 1555-1566.

[0214] In Scheme 10, the compound of formula LXXIV is reacted withcompound of formula XXIII (prepared in the same manner as described inScheme 4) to produce the compound of formula LXXX via reaction of step(g″). This rection is carried out in the same manner as describedhereinbefore in connection with the reaction of step (l) in Scheme 4.

[0215] The compound of formula LXXX is then selectively brominated at 0°C. using 30 wt % HBr in acetic acid dropwise to produce compound offormula LXXXI via reaction of step (h″). Any conventional method toconvert substituted acetone to 1-Bromoacetone can be utilized to carryout the reaction of step (h″).

[0216] The compound of formula LXXXI is converted to the compound offormula LXXXII via reaction of step (i″) in the same manner as describedhereinbefore in connection with the reaction of step (o) in Scheme 5.

[0217] The compound of formula LXXXII is converted to compound offormula LXXXIII via reaction of step (j″) in the same manner asdescribed in reaction of step (p) in Scheme 5.

[0218] The compound of formula LXXXIII is the compound of formula I′where R¹ is H.

[0219] The compound of formula LXXXIII can be converted to compound offormula LXXXIV where R⁷ is an alkyl chain having 1 to 7 carbon atoms byesterification of carboxylic acid with compound of formula XXX usingN,N-dicyclohexylcarbodiimide as dehydrating condensing agent. Anyconditions conventional for this reaction can be utilized to carry outthe reaction of step (k″).

[0220] The compound of formula LXXXIV is the compound of formula I′where R¹ is an alkyl group having 1 to 7 carbon atoms.

[0221] The compound of formula I′ where X is —CH₂CR¹²R¹³—, R⁹ ishydrogen, halo, or alkoxy having 1 to 3 carbon atoms, Q is OR¹ where R¹is hydrogen or alkyl having from 1 to 7 carbons, q is 0, m is 1, t is 0or 1 and n is 1 or 2, i.e. compounds of formula:

[0222] wherein A is as described above, R¹ is hydrogen or alkyl havingfrom 1 to 7 carbon atoms, and R¹² and R¹³ is independently hydrogen ormethyl can be prepared from the compound of the formula LXXIV, via thereaction scheme in Scheme 11.

[0223] In the reaction scheme of Scheme 11, A, t, R⁹, R¹², R¹³ and n areas above. R⁶ is an alkyl group containing from 1 to 7 carbon atoms, andY is a leaving group.

[0224] The compound formula LXXV is produced from compound of formulaLXXIV in the same manner as described hereinbefore in connection withthe reaction of step (b″) in Scheme 9.

[0225] The compound of formula LXXV is converted to compound of formulaLXXXV via reaction of step (i″) by selectively alkylating the compoundof formula LXXV with the compound of formula X. This reaction is carriedout utilizing a conventional base which converts substituted ketone togamma-keto ester. In carrying out this reaction it is generallypreferred to utilize lithium diisopropylamide as base. Alkylation willoccur at the less hindered methyl group. Generally this reaction iscarried out in an inert solvent such as tetrahydrofuran or1,2-dimethoxyethane at −78° C.

[0226] The compound of formula LXXXV is the compound of formula I′ whereR¹ is an alkyl group containing from 1 to 7 carbon atoms. The compoundof formula LXXXV can be converted to the free acid i.e. the compound offormula I′ where R¹ is H by ester hydrolysis. Any conventional method ofester hydrolysis will produce the compound of formula I′ where R¹ is H.

[0227] The compound of formula I where q is 1, R⁵ is an alkyl grouphaving 1 to 3 carbon atoms where X is —CH₂—, m is 1, t is 0 or 1 and nis 1 or 2, i.e. compounds of the formula:

[0228] wherein A is as above, R⁹ is hydrogen, halo, or alkoxy having 1to 3 carbon atoms and R¹ is ethyl can be prepared from the compoundformula XIII wherein, m is as above via the reaction scheme in Scheme12.

[0229] In Scheme 12, A is as above. Y¹ is chloro.

[0230] The compound of formula XIII (prepared in the same manner asdescribed hereinbefore in connection with the reaction of step (d) inScheme 3) can be converted to compound of formula LXXXVI via reaction ofstep (m″) in the same manner as described in the connection withreaction of step (l) in Scheme 4 hereinbefore.

[0231] In the step of (n″), the compound of formula LXXXVI is hydrolyzedto produce the compound of formula LXXXVII. Any conventional method ofbasic hydrolysis to hydrolyze ester can be utilized to carry out thisreaction.

[0232] The compound of formula LXXXVII is converted to acid chloride offormula LXXXVIII via reaction of step (o″) by reaction with thionylchloride. Any of the conventional method of converting acid to acidhalide can be utilized to carry out the reaction.

[0233] The compound of formula XVII is reacted with the compound offormula LXXXVIII to produce the compound of formula LXXXIX via reactionof step (p″). Any conventional base can be used to carry out thisreaction with the preferred base being pyridine. Any conventionalconditions to carry out the reaction of step (p″) can be utilized.

[0234] The compound of formula LXXXIX is the compound of formula I whereR¹ is ethyl.

[0235] The compound of formula I′ where q is 1, R⁵ is an alkyl grouphaving 1 to 3 carbon atoms, where X is —CH₂CR¹²R¹³—, R⁹ is hydrogen,halo, or alkoxy having 1 to 3 carbon atoms, Q is OR¹ where R¹ ishydrogen or alkyl having from 1 to 7 carbons, m is 1, t is 0 or 1 and nis 1 or 2, i.e. compounds of formula:

[0236] wherein A is as described above, R¹ is hydrogen or alkyl havingfrom 1 to 7 carbon atoms, and R¹² and R¹³ is independently hydrogen ormethyl can be prepared from the compound of the formula LXXIV, via thereaction scheme in Scheme 13.

[0237] In the reaction scheme of Scheme 13, R⁹, R¹², R¹³, R⁵, A, t, andn are as above. R⁶ is an alkyl group containing from 1 to 7 carbonatoms.

[0238] The compound formula LXXX is produced from compound of formulaLXXIV in the same manner as described hereinbefore in connection withthe reaction of step (g″) in Scheme 10.

[0239] The compound of formula LXXX is converted to compound of formulaXC via reaction of step (q″) by alkylating the compound of formula LXXXwith the compound of formula X. This reaction is carried out utilizing aconventional base which converts ketone to 3-keto ester. In carrying outthis reaction it is generally preferred to utilize lithiumdiisopropylamide as base. Alkylation will occur at the less hinderedmethyl group. Generally this reaction is carried out in an inert solventsuch as tetrahydrofuran or 1,2-dimethoxyethane at −78° C.

[0240] The compound of formula XC is the compound of formula I′ where R¹is an alkyl group containing from 1 to 7 carbon atoms. The compound offormula XC can be converted to the free acid i.e. the compound offormula I′ where R¹ is H by ester hydrolysis. Any conventional method ofester hydrolysis will produce the compound of formula I′ where R¹ is H.

[0241] The compound of formula II where Z is

[0242] m is 0, r is 1, q is 0, t is 0 or 1 and n is 1 or 2, R⁴ is—NHCO₂C(CH₃)₃, —NHCH₃, or —NHCH₂CH₃, i.e. the compounds of formula:

[0243] wherein A and R¹ are as above, can be prepared from the compoundof formula XXVI via reaction scheme in Scheme 14.

[0244] In Scheme 14, t, n, A and R¹ are as above. R⁷ is an alkyl grouphaving 1 to 7 carbon atoms. R⁸ is an alkyl group containing from 1 to 2carbon atoms. Y¹ is halo preferably bromo.

[0245] In Scheme 14, the compound of formula XXVI (prepared in the samemanner as described hereinbefore in connection with reaction of step (n)in Scheme 5) is reacted with the compound of formula XXXII in thepresence of a base to produce the compound of formula XXXIII viareaction of step (r). In carrying out this reaction it is generallypreferred to utilize triethylamine as base. Any conventional method ofreacting Boc-cys-OEt with halide can be utilized to carry out thisreaction.

[0246] The compound of formula XXXIII is compound of formula II where R⁴is —NHCO₂C(CH₃)₃ and R¹ is ethyl.

[0247] The compound of formula XXXIII can be converted to the free acidi.e. the compound of formula II where R¹ is H by ester hydrolysis. Anyconventional method of ester hydrolysis will produce the compound offormula II where R¹ is H and R⁴ is —NHCO₂C(CH₃)₃. The compound offormula XXXIII is converted to compound of formula XXXV first viareaction of step (s) by deprotecting t-butoxy group usingtrifluoroacetic acid and replacing by lower alkyl having 1 to 2 carbonatoms via reaction of step (t). Any conventional method to condenseamine with alkyl halide can be used to carry out this reaction.

[0248] The compound of formula XXXV is compound of formula II where R⁴is an amine having 1 to 2 carbon atoms and R¹ is an alkyl group having 2carbon atoms. The compound of formula XXXV can be converted to the freeacid i.e. the compound of formula XXXVI where R¹ is H by basichydrolysis via reaction of step (u). The compound of formula XXXVI iscompound of formula II where R⁴ is —NHCH₃ or —NHCH₂CH₃ and R¹ is H.

[0249] The compound of formula XXXVI can be converted to compound offormula XXXVII where R⁷ is an alkyl group having 1 to 7 carbon atoms byesterification of carboxylic acid with compound of formula XXX usingN,N-dicyclohexylcarbodiimide as dehydrating condensing agent. Anyconditions conventional for this reaction can be utilized to carry outthe reaction of step (v).

[0250] The compound of formula XXXVII is compound of formula II where R¹is an alkyl having 1 to 7 carbon atoms and R⁴ is —NHCH₃ or —NHCH₂CH₃.

[0251] The compound of formula II where Z is

[0252] m and q are 0, r is 1, t is 0 or 1, n is 1 or 2, i.e. compoundsof the formula:

[0253] A is as above, can be prepared from the compound of formula VIII,wherein t, n and A are as above, via the reaction scheme in Scheme 15.

[0254] In Scheme 15, the compound of formula VIII (prepared in the samemanner as described hereinbefore in connection with reaction of step (a)or (b) in Scheme 1) is converted to compound of formula XXVI in the samemanner as described in reaction of step (n) in Scheme 5.

[0255] The compound of formula XXVI is reacted with compound of formulaXXXVIII in the presence of base preferred base being triethylamine toproduce the compound of formula XXXIX. Any conventional method to reactthiol with halide can be utilized to carry out the reaction of step (w).

[0256] The compound of formula II where Z is

[0257] m is 0, r is 1, t is 0 or 1 and n is 1 or 2, R⁴ is H, i.e.compounds of formula:

[0258] wherein t, n, A and R¹ are as above, can be prepared from thecompound of formula VIII via the reaction scheme in Scheme 15.

[0259] In the reaction scheme of Scheme 15, t, n, A and R¹ are as above.R⁶ is an alkyl group having 1 to 7 carbon atoms.

[0260] The compound of formula VIII is prepared in same manner asdescribed hereinbefore in connection with the reaction of step (a) or(b) in Scheme 1.

[0261] The compound of formula XXVI is prepared from compound of formulaVIII in the same manner as described hereinbefore in connection with thereaction of step (n) in Scheme 5.

[0262] The compound of formula XXVI is reacted with compound of formulaXL in the presence of base preferred base being triethylamine to producecompound of formula XLI. Any conventional method to react thiol with1-bromoketone can be utilized to carry out the reaction of step (x).

[0263] The compound of formula XLI is the compound of formula II whereR¹ is an alkyl group containing from 1 to 7 carbon atoms. The compoundof formula XLI can be converted to the free acid i.e. the compound offormula II where R¹ is H by ester hydrolysis. Any conventional method ofester hydrolysis will produce the compound of formula II where R¹ is H.

[0264] The compound of formula II where Z is

[0265] r is 0, m is 1, t is 0 or 1 and n is 1 or 2, i.e. compounds offormula:

[0266] wherein n, t and A are as above, can be prepared from thecompound of formula XLII via the reaction scheme in Scheme 16.

[0267] In Scheme 16, t, n, and A are as above. Y is a leaving group suchas halide, mesyloxy or tosyloxy. Y¹ is halo preferably bromo.

[0268] In Scheme 16, the compound of formula XLII is converted tocompound of formula XLIII via the reaction of step (y) by selectivedisplacement of hydroxyl group of primary alcohol by halogen. Anyconventional halogenating agent can be utilized to carry out thisreaction with the preferred halogenating agent being phosphoroustribromide. This reaction is carried out in low temperature. Anyconditions conventional for this method can be utilized to carry out thereaction of step (y). The compound of formula XLIII was used immediatelywithout further purification.

[0269] The compound of formula XLIII is reacted with compound of formulaXXXVIII in the presence of base to produce the compound of formula XLIV.Any conventional method of condensing thiol with halide can be utilizedto carry out the reaction of step (z). Any conventional base can beutilized to carry out this reaction with the preferred base beingtriethylamine.

[0270] The compound of formula XLIV is converted to the compound offormula XLV by reaction with compound of formula VII via the reaction ofstep (a′). This reaction is carried out in the same manner as describedhereinbefore in connection with reaction of step (a) in Scheme 1.

[0271] The compound of formula II where Z is

[0272] r is 0, m is 1, t is 0 or 1 and n is 1 or 2, R⁴ is H, i.e. thecompounds of formula:

[0273] wherein A and R¹ are as above, can be prepared from the compoundof formula XLII via the reaction scheme in Scheme 16.

[0274] In Scheme 16, t, n, and A are as above. Y is a leaving group suchas halide, mesyloxy or tosyloxy. Y¹ is halo preferably bromo. R⁶ is analkyl group having 1 to 7 carbon atoms.

[0275] The compound of formula XLII is converted to compound of formulaXLIII in the same manner as described hereinbefore in connection withthe reaction of step (y).

[0276] The compound of formula XLIII is reacted with compound of formulaXL via reaction of step (b′) as described in connection with thereaction of step (x) in Scheme 15.

[0277] The compound of formula XLVI is converted to compound of formulaXLVII via reaction of step (c′). This reaction is carried out in thesame manner as described in the reaction of step (a) or (b) in Scheme 1.

[0278] The compound of formula XLVII is the compound of formula II whereR¹ is an alkyl group containing from 1 to 7 carbon atoms. The compoundof formula XLVII can be converted to the free acid i.e. the compound offormula II where R¹ is H by ester hydrolysis. Any conventional method ofester hydrolysis will produce the compound of formula II where R¹ is H.

[0279] The compound of formula II where Z is

[0280] r is 0, m is 1, t is 0 or 1 and n is 1 or 2, i.e. compounds offormula:

[0281] wherein t, n, A and R¹ are as above, R⁴ is —NHCO₂C(CH₃)₃, —NHCH₃,—NHCH₂CH₃, can be prepared from the compound of formula XLIII viareaction scheme in Scheme 17.

[0282] In Scheme 17, t, n, A and R¹ are as above. Y is a leaving groupsuch as halide, mesyloxy or tosyloxy. R⁷ is an alkyl group having 1 to 7carbon atoms and R⁸ is an alkyl group containing from 1 to 2 carbonatoms. Y¹ is halo preferably bromo.

[0283] In Scheme 17, the compound of formula XLIII (prepared in the samemanner as described hereinbefore in reaction of step (y) in Scheme 16)is reacted with the compound of formula XXXII in the presence of a baseto produce the compound of formula XLVIII via reaction of step (d′). Incarrying out this reaction it is generally preferred to utilizetriethylamine as base. Any conventional method of reacting Boc-cyst-OEtwith halide can be utilized to carry out this reaction.

[0284] The compound of formula XLIX is produced by reacting compound offormula XLVIII with compound of formula VII or IX. This reaction iscarried out in the same manner as described in the reaction of step (a)or (b) in Scheme 1.

[0285] The compound of formula XLIX is compound of formula II where R⁴is —NHCO₂C(CH₃)₃ and R¹ is an alkyl group having 2 carbon atoms.

[0286] The compound of formula XLIX can be converted to the free acidi.e. the compound of formula II, where R¹ is H by ester hydrolysis. Anyconventional method of ester hydrolysis will produce the compound offormula II where R¹ is H and R⁴ is —NHCO₂C(CH₃)₃.

[0287] The compound of formula XLIX is converted to compound of formulaL first via reaction of step (f′) by de protecting t-butoxy group usingtrifluoroacetic acid and replacing by lower alkyl containing from 1 to 2carbon atoms via reaction of step (g′). Any conventional method tocondense amine with alkyl halide can be used to carry out this reaction.

[0288] The compound of formula L is compound of formula II where R⁴ is

[0289] an amine having 1 to 2 carbon atoms and R¹ is an alkyl grouphaving 2 carbon atoms.

[0290] The compound of formula L can be converted to the free acid i.e.the compound of formula LI where R¹ is H by basic hydrolysis viareaction of step (h′).

[0291] The compound of formula LI is compound of formula II where R⁴ is—NHCH₃ or —NHCH₂CH₃ and R¹ is H. Any conventional method of esterhydrolysis will produce the compound of formula II where R¹ is H.

[0292] The compound of formula LI can be converted to compound offormula LII where R⁷ is an alkyl group having 1 to 7 carbon atoms byesterification of carboxylic acid with compound of formula XXX usingN,N-dicyclohexylcarbodiimide as dehydrating condensing agent. Anyconditions conventional for this reaction can be utilized to carry outthe reaction of step (i′).

[0293] The compound of formula LII is compound of formula II where R¹ isan alkyl group having 1 to 7 carbon atoms and R⁴ is —NHCH₃ or —NHCH₂CH₃.

[0294] The compound of formula III

[0295] wherein n is 1 or 2 and A is as above, can be prepared from thecompound of formula LIII, via reaction scheme in Scheme 18, wherein n, Aand Y are as above.

[0296] In Scheme 18, the compound of formula LIII is converted to thecompound of formula LIV in the same manner as described in connectionwith reaction of step (a) or (b) in Scheme 1.

[0297] The compound of formula LIV is converted to the compound offormula III via reaction of step (k′) by heating the compound of formulaLIV with sodium azide in the presence of ammonium chloride indimethylformamide. Any conventional conditions to convert nitrile toterazole can be utilized to carry out this reaction.

[0298] The compound of formula IV

[0299] wherein R¹ is as above, can be prepared from2′,6′-difluoroacetophenone via reaction scheme in Scheme 19.

[0300] In Scheme 19, R⁶ is an alkyl group having 1 to 7 carbon atoms.

[0301] The compound of formula LV is converted to compound of formulaLVI via reaction of step (l′) in same manner as described hereinbeforein connection with reaction of step (c) in Scheme 1.

[0302] The compound of formula LVI is the compound of formula IV whereR¹ is an alkyl group having 1 to 7 carbon atoms. The compound of formulaLVI can be converted to the free acid i.e. the compound of formula IVwhere R¹ is H by ester hydrolysis. Any conventional method of esterhydrolysis will produce the compound of formula IV where R¹ is H.

[0303] The compound of formula V

[0304] wherein n, A and R¹ are as above, R¹⁴ is hydroxy can be preparedfrom the compound of formula VI, via reaction scheme in Scheme 20.

[0305] In Scheme 20, n, A are as above. Y is a leaving group such ashalide, mesyloxy or tosyloxy. R⁷ is an alkyl group having 1 to 7 carbonatoms and R⁸ is an alkyl group having from 1 to 2 carbon atoms.

[0306] The compound of formula VI is converted to compound of formulaVIII in same manner as described hereinbefore in connection with thereaction of step (a) or (b) of Scheme 1.

[0307] The compound of formula VIII is reacted with compound of formulaLVII via reaction of step (m′) in the presence of freshly preparedsodium alkoxide at room temperature to produce compound of formulaLVIII. Any conventional conditions for this alkylation reaction can beutilized to carry out the reaction.

[0308] The compound of formula LVIII is the compound of formula V whereR¹ is an alkyl group having 1 to 2 carbon atoms. The compound of formulaLVIII can be converted to the free acid i.e. the compound of formula Vwhere R¹ is H by ester hydrolysis via reaction of step (n′). Anyconventional method of ester hydrolysis will produce the compound offormula V where R¹ is H.

[0309] The compound of formula LVIII can be converted to compound offormula LIX where R⁷ is an alkyl group having 1 to 7 carbon atoms byesterification of carboxylic acid with compound of formula XXX usingN,N-dicyclohexylcarbodiimide as dehydrating condensing agent. Anyconditions conventional for this reaction can be utilized to carry outthe reaction of step (o′).

[0310] The compound of formula LIX is the compound of formula V where R¹is an alkyl group having 1 to 7 carbon atoms.

[0311] The compound of formula I′ where X is —CH₂CH₂—, R⁹ is hydrogen,halo, or alkoxy having 1 to 3 carbon atoms, q and m are 0, t is 0 or 1,and n is 1 or 2, i.e. compounds of formula:

[0312] wherein Q is NR¹⁰R¹¹ where R¹⁰ is hydrogen and R¹ is hydroxylgroup. t, n, A, and R⁹ are as described above, can be prepared from thecompound of the formula

[0313] via the reaction scheme of Scheme 21.

[0314] In the reaction scheme 21, A, t, R⁹, R⁶ and n are as above.

[0315] The compound of formula XI is prepared in the same manner asdescribed in the reaction scheme of Scheme 1.

[0316] The compound of formula XI can be converted to the compound offormula XCII via reaction step (s″) by treating the compound of formulaXI with hydroxylamine hydrochloride in an organic solvent, for exampleethanol, tetrahydrofuran or the like. The reaction is carried out usingorganic base for example, potassium hydroxide or the like. Anyconditions conventional for the synthesis of hydroxamic acids can beutilized to carry out this reaction.

[0317] The compound of formula I′ where X is —CH₂—CH₂—, q and m are 0, tis 0 or 1, and n is 1 or 2, R⁹ is hydrogen, halo, or alkoxy having 1 to3 carbon atoms, i.e. compounds of formula:

[0318] wherein t, n, A, and R⁹ are described as above. Q is NR¹⁰R¹¹where R¹⁰ and R¹¹ are hydrogen.

[0319] can be prepared from the compound of the formula

[0320] via the reaction scheme in Scheme 21.

[0321] In the reaction scheme of Scheme 21, A, t, R⁹ and n are as above.R¹ is H, R⁶ is an alkyl having 1 to 7 carbon atoms.

[0322] The compound of formula XI is prepared in the same manner asdescribed in the reaction scheme of Scheme 1. The compound of formula XIis the compound of formula I′ where R¹ is an alkyl group containing from1 to 7 carbon atoms. The compound of formula XI can be converted to thefree acid i.e. the compound of formula I′ where R¹ is H by esterhydrolysis.

[0323] The compound of formula XI can be converted to compound offormula XCIII via reaction step (t″) by first activating by for example,benzotriazole-1-yloxytrispyrrolidinophosphonium hexafluorophosphate, orthe like in an organic solvent, for example, methylene chloride,N,N-dimethylformamide or the like followed by addition of aqueousammonium hydroxide or ammonia. The reaction is carried out using organicbase for example, triethylamine, diisopropylethylamine or the like.

[0324] Any conditions conventional to synthesize amide can be utilizedto carry out the reaction of step (t″).

[0325] The compound of formula I′ where X is —CH₂—CH₂—, q and m are 0, tis 0 or 1, and n is 1 or 2, R⁹ is hydrogen, halo, or alkoxy having 1 to3 carbon atoms, i.e. compounds of formula:

[0326] wherein t, n, A, and R⁹ are described as above. Q is NR¹⁰R¹¹where R¹⁰ and R¹¹ are independently hydrogen or alkyl having 1 to 3carbon atoms.

[0327] can be prepared from the compound of the formula

[0328] via the reaction scheme in Scheme 21.

[0329] In the reaction scheme of Scheme 21, A, t, R⁹ and n are as above.R¹ is H and R⁶ is an alkyl having 1 to 7 carbon atoms.

[0330] The compound of formula XI is prepared in the same manner asdescribed in the reaction scheme of Scheme 1. The compound of formula XIis the compound of formula I′ where R¹ is an alkyl group containing from1 to 7 carbon atoms. The compound of formula XI can be converted to thefree acid i.e. the compound of formula I′ where R¹ is H by esterhydrolysis.

[0331] The compound of formula XI can be converted to the compound offormula XCIV either by first reacting with a chlorinating reagent forexample, thionyl chloride or the like then reacting acid halide withcorresponding amine. Any conventional method of condensing amine with anacid halide can be utilized to carry out the reaction of step (u″) or bycondensing corresponding amine with the compound of formula XI using1,3-Dicyclohexylcarbodiimide as condensing agent.

[0332] Any conventional method of condensing amine with an acid can beutilized to carry out the reaction of step (u″).

[0333] The compound of formula I′ where X is —CH₂—CH₂—, q is 1, R⁵ is analkyl group having 1 to 3 carbon atoms, R⁹ is hydrogen, halo, or alkoxyhaving 1 to 3 carbon atoms, m is 0, t is 0 or 1, and n is 1 or 2, i.e.compounds of formula:

[0334] wherein Q is NR¹⁰R¹¹ where R¹⁰ is hydrogen and R¹¹ is hydroxylgroup. A, t, n, and R⁹ are as described above, can be prepared from thecompound of the formula

[0335] via the reaction scheme in Scheme 22.

[0336] In the reaction scheme 22, q, A, t, R⁵, R⁹ and n are described asabove. R⁶ is an alkyl having 1 to 7 carbon atoms.

[0337] The compound of formula XXV is prepared in the same manner asdescribed in the reaction scheme of Scheme 4.

[0338] The compound of formula XXV can be converted to the compound offormula XCV via reaction step (v″) in the same manner as described inreaction step (s″) of Scheme 21.

[0339] The compound of formula I′ where X is —CH₂—CH₂—, q is 1, R⁵ is analkyl group having 1 to 3 carbon atoms, R⁹ is hydrogen, halo, or alkoxyhaving 1 to 3 carbon atoms, m is 0, t is 0 or 1, and n is 1 or 2, R¹ isH, i.e. compounds of formula:

[0340] wherein q, t, n, A, R⁵ and R⁹ are described as above. Q isNR¹⁰R¹¹ where R¹⁰ and R¹¹ are hydrogen and can be prepared from thecompound of the formula

[0341] via the reaction scheme in Scheme 22.

[0342] In the reaction scheme of Scheme 22, q, A, t, R⁵, R⁹ and n are asabove. R¹ is H and R⁶ is an alkyl having 1 to 7 carbon atoms.

[0343] The compound of formula XXV is prepared in the same manner asdescribed in the reaction scheme of Scheme 4. The compound of formulaXXV is the compound of formula I′ where R¹ is an alkyl group containingfrom 1 to 7 carbon atoms. The compound of formula XXV can be convertedto the free acid i.e. the compound of formula I′ where R¹ is H by esterhydrolysis.

[0344] The compound of formula XXV can be converted to the compound offormula XCVI via reaction step (w″) in the same manner as described instep (t″) of reaction scheme 21.

[0345] The compound of formula I′ where X is —CH₂—CH₂—, q is 1, R⁵ is analkyl group having 1 to 3 carbon atoms, R⁹ is hydrogen, halo, or alkoxyhaving 1 to 3 carbon atoms, m is 0, t is 0 or 1, and n is 1 or 2, i.e.compounds of formula:

[0346] wherein q, t, n, A, R⁵ and R⁹ are as described above, Q isNR¹⁰R¹¹ where R¹⁰ and R¹¹ are independently hydrogen or alkyl having 1to 3 carbon atoms.

[0347] can be prepared from the compound of the formula

[0348] via the reaction scheme in Scheme 22.

[0349] In the reaction scheme 22, q, A, t, R⁵, R⁹ and n are as above. R⁶is an alkyl having 1 to 7 carbon atoms. R¹ is H.

[0350] The compound of formula XXV is prepared in the same manner asdescribed in the reaction scheme of Scheme 4. The compound of formulaXXV is the compound of formula I′ where R¹ is an alkyl group containingfrom 1 to 7 carbon atoms. The compound of formula XXV can be convertedto the free acid i.e. the compound of formula I′ where R¹ is H by esterhydrolysis.

[0351] The compound of formula XXV can be converted to the compound offormula XCVII via reaction step (x″) in the same manner as described instep. (u″) of reaction scheme 21.

[0352] The compound of formula I′ where X is —CH₂—CH₂—, R⁹ is hydrogen,halo, or alkoxy having 1 to 3 carbon atoms, m is 1, q is 0, t is 0 or 1and n is 1 or 2, i.e. compounds of the formula:

[0353] wherein Q is NR¹⁰R¹¹ where R¹⁰ is hydrogen, R¹¹ is hydroxylgroup. t, n, A, and R⁹ are as described above, can be prepared from thecompound of the formula

[0354] via the reaction scheme in Scheme 23.

[0355] In the reaction scheme 23, A, t, R⁹ and n are as described above.R is an alkyl having 1 to 7 carbon atoms.

[0356] The compound of formula LXXXV is prepared in the same manner asdescribed in the reaction scheme of Scheme 11.

[0357] The compound of formula LXXXV can be converted to the compound offormula XCVIII via reaction step (y″) in the same manner as described inreaction step (s″) of Scheme 21.

[0358] The compound of formula I′ where X is —CH₂—CH₂—, R⁹ is hydrogen,halo, or alkoxy having 1 to 3 carbon atoms, m is 1, q is 0, t is 0 or 1and n is 1 or 2, i.e. compounds of the formula:

[0359] wherein t, n, A, and R⁹ are described as above. Q is NR¹⁰R¹¹where R¹⁰ and R¹¹ are hydrogen.

[0360] can be prepared from the compound of the formula

[0361] via the reaction scheme in Scheme 23.

[0362] In the reaction scheme of Scheme 23, A, t, R⁵, R⁹ and n are asabove. R¹ is H. R⁶ is an alkyl having 1 to 7 carbon atoms.

[0363] The compound of formula LXXXV is prepared in the same manner asdescribed in the reaction scheme of Scheme 11. The compound of formulaLXXXV is the compound of formula I′ where R¹ is an alkyl groupcontaining from 1 to 7 carbon atoms. The compound of formula LXXXV canbe converted to the free acid i.e. the compound of formula I′ where R¹is H by ester hydrolysis.

[0364] The compound of formula LXXXV can be converted to the compound offormula XCIX via reaction step (z″) in the same manner as described inreaction step (t″) of reaction scheme 21.

[0365] The compound of formula I′ where X is —CH₂—CH₂—, R⁹ is hydrogen,halo, or alkoxy having 1 to 3 carbon atoms, m is 1, q is 0, t is 0 or 1and n is 1 or 2, i.e. compounds of the formula:

[0366] wherein t, n, A, and R⁹ are as described above, Q is NR¹⁰R¹¹where R¹⁰ and R¹¹ are independently hydrogen or alkyl having 1 to 3carbon atoms.

[0367] can be prepared from the compound of the formula

[0368] via the reaction scheme in Scheme 23.

[0369] In the reaction scheme 23, A, t, R⁹ and n are as above. R¹ is H.R⁶ is an alkyl having 1 to 7 carbon atoms.

[0370] The compound of formula LXXXV is prepared in the same manner asdescribed in the reaction scheme of Scheme 11. The compound of formulaLXXXV is the compound of formula I′ where R is an alkyl group containingfrom 1 to 7 carbon atoms. The compound of formula LXXXV can be convertedto the free acid i.e. the compound of formula I′ where R¹ is H by esterhydrolysis.

[0371] The compound of formula LXXXV can be converted to the compound offormula C via reaction step (a′″) in the same manner as described instep (u″) of reaction scheme 21.

[0372] The compound of formula I′ where X is —CH₂—CH₂—, R⁹ is hydrogen,halo, or alkoxy having 1 to 3 carbon atoms, q is 1, R⁵ is an alkyl grouphaving 1 to 3 carbon atoms, m is 1, t is 0 or 1, and n is 1 or 2, i.e.compounds of formula:

[0373] wherein Q is NR¹⁰R¹¹ where R¹⁰ is hydrogen and R¹¹ is hydroxylgroup. t, n, A, R⁵ and R⁹ are as described above,

[0374] can be prepared from the compound of the formula

[0375] via the reaction scheme in Scheme 24.

[0376] In the reaction scheme 24, q, A, t, n, R⁵, R⁹, and R⁶ aredescribed as above.

[0377] The compound of formula XC is prepared in the same manner asdescribed in the reaction scheme of Scheme 13.

[0378] The compound of formula XC can be converted to the compound offormula CII via reaction step (b′″) in the same manner as described inreaction step (s″) of Scheme 21.

[0379] The compound of formula I′ where X is —CH₂—CH₂—, R⁹ is hydrogen,halo, or alkoxy having 1 to 3 carbon atoms, q is 1, R⁵ is an alkyl grouphaving 1 to 3 carbon atoms, m is 1, t is 0 or 1, and n is 1 or 2, i.e.compounds of formula:

[0380] wherein q, t, n, A, R⁵ and R⁹ are described as above. Q isNR¹⁰R¹¹ where R¹⁰ and R¹¹ are hydrogen.

[0381] can be prepared from the compound of the formula

[0382] via the reaction scheme in Scheme 24.

[0383] In the reaction scheme of Scheme 24, q, A, t, R⁵, R⁹ and n are asabove. R¹ is H. R⁶ is an alkyl having 1 to 7 carbon atoms.

[0384] The compound of formula XC is prepared in the same manner asdescribed in the reaction scheme of Scheme 13. The compound of formulaXC is the compound of formula I′ where R¹ is an alkyl group containingfrom 1 to 7 carbon atoms. The compound of formula XC can be converted tothe free acid i.e. the compound of formula I′ where R¹ is H by esterhydrolysis.

[0385] The compound of formula XC can be converted to the compound offormula CIII via reaction step (c′″) in the same manner as described instep (t″) of reaction scheme 21.

[0386] The compound of formula I′ where X is —CH₂—CH₂—, R⁹ is hydrogen,halo, or alkoxy having 1 to 3 carbon atoms, q is 1, R⁵ is an alkyl grouphaving 1 to 3 carbon atoms, m is 1, t is 0 or 1, and n is 1 or 2, i.e.compounds of formula:

[0387] wherein q, t, n, A, R⁵ and R⁹ are as described above, Q isNR¹⁰R¹¹ where R¹⁰ and R¹¹ are independently hydrogen or alkyl having 1to 3 carbon atoms.

[0388] can be prepared from the compound of the formula

[0389] via the reaction scheme in Scheme 24.

[0390] In the reaction scheme 24, q, A, t, R⁵, R⁹ and n are as above. R¹is H. R⁶ is an alkyl having 1 to 7 carbon atoms.

[0391] The compound of formula XC is prepared in the same manner asdescribed in the reaction scheme of Scheme 13. The compound of formulaXC is the compound of formula I′ where R¹ is an alkyl group containingfrom 1 to 7 carbon atoms. The compound of formula XC can be converted tothe free acid i.e. the compound of formula I′ where R¹ is H by esterhydrolysis.

[0392] The compound of formula XC can be converted to the compound offormula CIV via reaction step (d′″) in the same manner as described instep (u″) of reaction scheme 21.

[0393] The compound of formula V′ where n is 1 or 2, t is 0, R¹, R⁹ andR¹⁴ are H, i.e. compounds of formula:

[0394] wherein t, n, A, R⁹, R¹⁴ and R¹ are as described above,

[0395] can be prepared from the compound of the formula

[0396] via the reaction scheme in Scheme 25.

[0397] In the reaction scheme of Scheme 25, A, t, and n are as above. R⁶is an alkyl group containing from 1 to 7 carbon atoms.

[0398] The compound of formula XI is prepared in the same manner asdescribed in the reaction scheme of Scheme 1.

[0399] The compound of formula XI can be converted to compound offormula CV via reaction step (e40 ″), by treating the compound offormula XI with bromine or the like in an organic solvent, for exampleether, carbon tetrachloride with the preferred organic solvent beingether.

[0400] As the reaction temperature, ice cooling to room temperature canbe used with the preferred being ice cooling.

[0401] The compound of formula CV can be converted to the compound offormula CVI via reaction step (f′″), by dehydrobromination. The reactionis carried out using conventional base preferred base beingtriethylamine or the like in an organic solvent for example carbontetrachloride or the like. Any of the conditions conventional indehydrobromination can be utilized to carry out the reaction of step(f″).

[0402] The compound of formula CVI is the compound of formula V′ whereR¹ is an alkyl group containing from 1 to 7 carbon atoms. The compoundof formula CVI can be converted to the free acid i.e. the compound offormula V′ where R¹ is H by ester hydrolysis. Any conventional method ofester hydrolysis will produce the compound of formula V′ where R¹ is H.

[0403] The compound of formula CXVI where X is —CH₂—CH₂—, t is 0 or 1,and n is 1 or 2, R¹ and R⁹ are H, i.e. compounds of formula:

[0404] wherein t, n, A, and R⁹ are as described above, R¹ is H.

[0405] can be prepared from the compound of the formula

[0406] via the reaction scheme in Scheme 26.

[0407] In the reaction scheme of 26, A, t, n and R⁹ are as above. R¹ isH. R⁶ is an alkyl group having 1 to 7 carbon atoms.

[0408] The compound of formula XI is prepared in the same manner asdescribed in the reaction scheme of Scheme 1. The compound of formula XIis the compound of formula I′ where R¹ is an alkyl group containing from1 to 7 carbon atoms. The compound of formula XI can be converted to thefree acid i.e. the compound of formula I′ where R¹ is H by esterhydrolysis. Any conventional method of ester hydrolysis will produce thecompound of formula I′ where R¹ is H.

[0409] The compound of formula XI is converted to compound of formulaCVII via reaction step (g″) via Wolff-Kishner reduction by treating thecompound of formula XI with hydrazine hydrate and potassium hydroxide inan organic solvent for example, ethylene glycol or the like. Any of theconditions conventional in Wolff-Kishner reductions can be utilized tocarry out the reaction of step (g′″).

[0410] The compound of formula XCI where n is 1 or 2, R⁹ is H and R¹ ishydrogen or alkyl having 1 to 3 carbon atoms, i.e. compounds of formula:

[0411] wherein n, A, R⁹ and R¹ are as described above,

[0412] can be prepared from the compound of the formula

[0413] via the reaction scheme in Scheme 27.

[0414] In the reaction scheme of Scheme 27, R⁹ is a hydrogen atom, t is0, R⁶ is an alkyl having 1 to 7 carbon atoms, A and n are as describedabove.

[0415] The compound of formula XI is prepared in the same manner asdescribed in the reaction scheme of Scheme 1.

[0416] The compound of formula XI can be converted to the compound offormula CVIII via reaction step (h′″) by selectively reducing ketonegroup to an alcohol. This reaction is carried out utilizing conventionalreducing agents for example, sodium borohydride in ethanol,Bis-3-methyl-2-butyl-borane in tetahydrofuran or the like. Any of theconditions conventional in such selective reduction reactions can beutilized to carry out the reaction of step (h′″).

[0417] The compound of formula CVIII can be converted to compound offormula CIX via reaction step (i′″) by bromination of compound offormula CVIII with brominating reagents for example, phosphoroustribromide in tetrahydrofuran or dioxane, hydrogen bromide in aceticacid or dioxane, carbon tetrabromide andbis-(1,2-diphenylphosphino)ethane or the like. Any of the conditionsconventional in such bromination reactions can be utilized to carry outthe reaction of step (i′″).

[0418] The compound of formula CIX can be converted to the compound offormula CX via reaction step (j′″), by dehydrobromination. The reactionis carried out using conventional base preferred base beingtriethylamine or the like in an organic solvent for example carbontetrachloride or the like. Any of the conditions conventional in suchdehydrobromination reactions can be utilized to carry out the reactionof step (j′″).

[0419] The compound of formula CX is the compound of formula XCI whereR¹ is an alkyl group containing from 1 to 3 carbon atoms. The compoundof formula CX can be converted to the free acid i.e. the compound offormula XCI where R¹ is H by ester hydrolysis. Any conventional methodof ester hydrolysis will produce the compound of formula XCI where R¹ isH.

[0420] The compound of formula CXVII where X is —CH₂—CH₂—, and n is 0 or2, R¹⁵ is a hydrogen or lower alkyl group having 1 to 3 carbon atoms, R⁹is hydroxy, hydrogen, alkoxy group having 1 to 3 carbon atoms, halogenatom, R¹ is hydrogen or alkyl having 1 to 3 carbon atoms, i.e. compoundsof formula:

[0421] wherein n, A, R⁹ and R¹⁵ are as described above,

[0422] can be prepared by reacting the compound of the formula

[0423] with compound of formula

[0424] via the reaction scheme in Scheme 28.

[0425] In the reaction scheme of Scheme 28, A, n, R⁹, R¹⁵ are describedas above, R is an alkyl having 1 to 3 carbon atoms.

[0426] The compound of formula CXI can be converted to compound offormula CXIII via reaction step (k′″) by treating compound of formulaCXI with condensing agent, for example diethyl cyanophosphate,1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide or the like in an organicsolvent, for example, methylene chloride, N,N-dimethylformamide followedby addition of compound of formula CXII.

[0427] The reaction temperature can be from 0° C. to room temperature.

[0428] The compound of formula CXIII can be converted to the compound offormula CXIV via reaction of step (l′″) by alkylating the compound offormula CXIII with the compound of formula X. This reaction is carriedout in the same manner as described in the reaction step (c) of reactionscheme 1.

[0429] The compound of formula CXIV is the compound of formula CXVIIwhere R⁹ is an alkoxy group having 1 to 3 carbon atoms, halogen atom.The R can be converted to hydroxy via demethylation by using forexample, boron tribromide in methylene chloride or the like. Any of theconditions conventional in such demethylation reactions can be utilizedto carry out the reaction.

[0430] The compound of formula CXIV is the compound of formula CXVIIwhere R¹ is an alkyl group having 1 to 3 carbon atoms. The compound offormula CXIV can be converted to the free acid i.e. the compound offormula CXVII where R¹ is H by ester hydrolysis. Any conventional methodof ester hydrolysis will produce the compound of formula CXVII where R¹is H.

[0431] Compounds of general formula CXI can be prepared byetherification of compound of formula CI by using alkyl halide followedby an ester hydrolysis.

[0432] wherein R¹⁶ is a lower alkyl group having 1 to 3 carbon atoms. R⁹is a hydroxyl group.

[0433] The reaction between compound of formula CI and alkyl halide canbe carried like in an organic solvent, for example N,N-dimethylformamideor the like, using base, for example potassium carbonate, cesiumcarbonate or the like. Any of the conditions conventional in suchalkylation reactions can be utilized to carry out this reaction. Esterhydrolysis can be conducted under acidic conditions for example,hydrochloric acid or hydrochloric acid mixed with organic solvent forexample, ethanol or using acetic acid or the like. The reaction can becarried out at room temperature to solvent refluxing temperature. Anyconventional conditions for acidic ester hydrolysis can be utilized tocarry out this reaction. Further, if needed, ester hydrolysis can becarried out using basic conditions, for example, in an aqueous solutionof sodium hydroxide or a mixed solution of sodium hydroxide in anorganic solvent for example, ethanol or the like. Any conditionsconventional for basic hydrolysis can be utilized to carry out thisreaction

[0434] Compounds of general formula CXII can be prepared by reactingcompound of formula VII with chlorinating agent for example,trimethylsilyl chloride, thionyl chloride or the like in an organicsolvent for example, dimethyl sulfoxide, N,N-dimethylformamide or thelike. The reaction temperature can be room temperature to organicrefluxing temperature. Any conditions conventional for chlorinationreactions can be utilized to carry out the reaction.

[0435] The chloromethyl intermediate was converted to compound offormula CXII via Gabriel synthesis by treating chloromethyl intermediatewith potassium phthalimide in an organic solvent for example,N,N-dimethylformamide, dioxane or the like. The phthalimide is thenreacted with hydrazine by an exchange reaction in an organic solvent forexample, ethanol, dioxane or the like to produce the compound of formulaCXII. Any of the conditions conventionally used in the Gabriel synthesiscan be utilized to carry out the reaction.

[0436] The invention will be better understood by reference to thefollowing examples which illustrate but do not limit the inventiondescribed herein.

CHEMICAL SYNTHESIS EXAMPLES Example 1 Synthesis of4-(4-(2-Fluorobenzyloxy)phenyl)-4-oxobutyric Acid

[0437]

[0438] Step A: Preparation of 4-(2-Fluorobenzyloxy)acetophenone:

[0439] A solution of 4-Hydroxyacetophenone (2.80 g, 20.6 mmol) in dryDMF (15 ml) was added at room temperature to a suspension of NaH (60% inoil, 0.794 g) in dry DMF (20 ml). When evolution of hydrogen ceased,2-Fluorobenzyl bromide (3 g, 15.8 mmol) was added drop wise. Thereaction mixture was stirred at room temperature for 6 hours, quenchedwith sat aq. NH₄Cl and concentrated in vacuo. The crude residue wastaken in EtOAc and washed with water and brine. The organic layer wasdried over Na₂SO₄, filtered and concentrated. The residue was purifiedby flash chromatography on silica gel column (hex:ethyl acetate, 2:1) toprovide the title compound as an off white solid.

[0440]¹H NMR (270 MHz, CDCl₃): 2.5 (s, 3H); 5.2 (s, 2H); 6.9-7.1 (m,4H); 7.2-7.3 (m, 1H); 7.4 (t, 1H); 7.9 (d, 2H).

[0441] Step B: Preparation of Tert-Butyl4-(4-(2-fluorobenzyloxy)phenyl)-4-oxobutyrate:

[0442] To a stirred solution of 4-(2-fluorobenzyloxy)acetophenone (StepA, 1.5 g, 6.1 mmol) in dry THF (20 ml) and DMPU (5 ml) was added asolution of lithium bis(trimethylsilyl)amide (1.0M, 7 ml) at −60° C.under argon. After 10 minutes of stirring at −60° C., tert-Butylbromoacetate (4.75 g, 24.4 mmol) was added rapidly. The reaction mixturewas stirred for an additional 10 minutes and then warmed to roomtemperature for 4 hours. The crude mixture was taken in EtOAc and washedwith water and brine. The aqueous layer was extracted one more time withEtOAc. The combined organic layers were dried over Na₂SO₄, filtered,concentrated and purified by flash chromatography on a silica gel column(hex:ethyl acetate, 2:1) to provide the title compound.

[0443]¹H NMR (270 MHz, CDCl₃): 1.4 (s, 9H); 2.7 (t, 2H); 3.2 (t, 2H);5.1 (s, 2H); 6.9-7.1 (m, 4H); 7.2-7.3 (m, 1H); 7.4 (t, 1H); 7.9 (d, 2H).

[0444] Step C: Preparation of4-(4-(2-Fluorobenzyloxy)phenyl)-4-oxobutyric Acid:

[0445] A solution of tert-Butyl4-(4-(2-fluorobenzyloxy)phenyl)-4-oxobutyrate (Step B, 1.27 g, 4.2 mmol)in dichloromethane (25 ml) was treated with trifluoroacetic acid (5 ml).The reaction mixture was stirred at ambient temperature for 3 hours andconcentrated in vacuo.

[0446] The purification was done by flash chromatography on silica gelcolumn (chloroform:methanol, 95:5 spiked with acetic acid) to afford thetitle compound as a white powder.

[0447]¹H NMR (270 MHz, CDCl₃:CD₃OD): 2.6 (t, 2H); 3.2 (t, 2H); 5.1 (s,2H); 6.9-7.1 (m, 4H); 7.2-7.3 (m, 1H); 7.4 (t, 2H); 7.9 (d, 2H).

Example 2 Synthesis of 4-(4-(2-Methoxybenzyloxy)phenyl)-4-oxobutyricAcid

[0448]

[0449] Step A: Preparation of 4-(2-Methoxybenzyloxy)acetophenone:

[0450] A solution of 2-Methoxybenzyl alcohol (2.99 g, 21.7 mmol) in dryTHF (5 ml) and dry DMF (5 ml) was added to a stirred solution of4-Hydroxyacetophenone (3.25 g, 23.8 mmol), triphenylphosphine (7.36 g,28.0 mmol), and diethyl azodicarboxylate (4.51 g, 25.9 mmol) in dry THF(20 ml) at 5-10° C. The reaction mixture was stirred at 0° C. for 2hours, warmed to room temperature and concentrated in vacuo. The residuewas taken in EtOAc and washed twice with saturated NaHCO₃. The organiclayer was dried over Na₂SO₄, filtered, concentrated and purified byflash chromatography on a silica gel column (choloroform:methanol, 99:1)to provide the title compound as a white solid.

[0451]¹H NMR (270 MHz, CDCl₃): 2.5 (s, 3H); 3.9 (s, 3H); 5.2 (s, 2H);6.9-7.1 (m, 4H); 7.3 (m, 1H); 7.4 (d, 1H); 7.9 (d, 2H).

[0452] Step B: Preparation of Ethyl4-(4-(2-methoxybenzyloxy)phenyl)-4-oxobutyrate:

[0453] To a stirred solution of 4-(2-Methoxybenzyloxy)acetophenone (StepA, 1.22 g, 4.7 mmol) in dry THF (20 ml) and DMPU (5 ml) was added asolution of lithium bis(trimethylsilyl)amide (1.0M, 5 ml) under argon at−60° C. After 10 minutes of stirring at −60° C., ethyl bromoacetate(2.59 g, 15.6 mmol) was added rapidly. The reaction mixture was stirredfor an additional 10 minutes and then warmed to room temperature for 2hours. The crude mixture was taken in EtOAc and washed with water. Theaqueous layer was extracted one more time with EtOAc and combinedorganic layers were dried over Na₂SO₄, filtered and concentrated. Thepurification was done by flash chromatography on silica gel column(hex:ethyl acetate, 4:1) to provide the title compound as a white solid.

[0454]¹H NMR (270 MHz, CDCl₃): 1.2 (t, 3H); 2.6 (t, 2H); 3.2 (t, 2H);3.8 (s, 3H); 4.1 (q, 2H); 5.1 (s, 2H); 6.9-7.0 (m, 4H); 7.1-7.3 (m, 2H);7.9 (d, 2H).

[0455] Step C: Preparation of4-(4-(2-Methoxybenzyloxy)phenyl)-4-oxobutyric Acid:

[0456] A solution of Ethyl4-(4-(2-methoxybenzyloxy)phenyl)-4-oxobutyrate (Step B, 1.49 g, 4.3mmol) in abs ethanol (20 ml) was treated with 1N NaOH (6 ml). Thereaction mixture was stirred at room temperature for 2 hours and thenacidified with 1M HCl. The resulting white solid was filtered, washedwith cold water and dried under vacuum to provide the title compound.

[0457]¹H NMR (270 MHz, CDCl₃: CD₃OD): 2.6 (t, 2H); 3.2 (t, 2H); 3.8 (s,3H); 5.1 (s, 2H); 6.97.0 (m, 4H); 7.2-7.3 (m, 2H); 7.8 (d, 2H).

Example 3 Synthesis of3-[(4-(2-Fluorobenzyloxy)phenyl)-methylthio]propionic Acid

[0458]

[0459] Step A: Preparation of 4-Hydroxybenzyl Bromide:

[0460] To a stirred solution of PBr₃ (1.38 g, 5.0 mmol) in dry THF (2ml) at −5° C. was added a solution of dry pyridine (0.201 ml) in dry THF(0.4 ml). A solution of 4-Hydroxybenzyl alcohol (1.89 g, 15.2 mmol) indry THF (23 ml) was added drop wise to the reaction mixture. Thereaction mixture was allowed to stand at room temperature for 18 hours,then diluted with THF and filtered through celite pad. The filtrate wasevaporated, the resulting semisolid was redissolved in dry toluene (16ml). The solution was maintained at −20° C. for 2 hours, and thenfiltered through celite pad to provide the title compound as a lightyellow solution which was used without further purification.

[0461] Step B: Preparation of Ethyl3-((4-hydroxyphenyl)-methylthio)propionate:

[0462] To a solution of NaH (60% dispersed in oil, 0.731 g, 21.7 mmol)in dry DMF (15 ml) was added Ethyl 0.3-mercaptopropionate (2.66 g, 19.8mmol). When the evolution of hydrogen ceased, 4-Hydroxybenzyl bromidefrom Step A was added. The reaction mixture was stirred for 16 hours atroom temperature, quenched with sat. NH₄Cl and concentrated in vacuo.The crude residue was taken in EtOAc and washed with water and brine.The aqueous layer was washed one more time with EtOAc. The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated. Thepurification was done by flash chromatography on silica gel column(dichloromethane:ethyl acetate, 95:5) to provide the title compound.

[0463]¹H NMR (270 MHz, CDCl₃): 1.2 (t, 3H); 2.4-2.6 (m, 4H); 3.6 (s,2H); 4.1 (q, 2H); 6.7 (d, 2H); 7.2 (d, 2H).

[0464] Step C: Preparation of Ethyl3-((4-(2-fluorobenzyloxy)phenyl)-methylthio)propionate:

[0465] To a solution of NaH (60% dispersed in oil, 0.054 g, 1.3 mmol) indry DMF (10 ml) was added Ethyl3-((4-hydroxyphenyl)-methylthio)propionate (Step B, 2.5 g, 1.0 mmol).When the evolution of hydrogen ceased, 2-Fluorobenzyl bromide (0.263 g,1.3 mmol) was added. The reaction mixture was stirred for 4 hours atroom temperature, quenched with sat. NH₄Cl, and concentrated in vacuo.The crude residue was taken in EtOAc and washed twice with water andbrine. The aqueous layer was washed one more time with EtOAc. Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated. The purification was done by flash chromatography onsilica gel column (hex:ethyl acetate, 4:1) to provide the titlecompound.

[0466]¹H NMR (270 MHz, CDCl₃): 1.2 (t, 3H); 2.4-2.6 (m, 4H); 3.6 (s,2H); 4.2 (q, 2H); 5.15 (s, 2H); 6.9 (d, 2H); 7.2-7.4 (m, 5H); 7.5 (t,1H).

[0467] Step D: Preparation of3-((4-(2-fluorobenzyloxy)phenyl)-methylthio)propionic Acid:

[0468] To a solution of Ethyl3-((4-(2-fluorobenzyloxy)phenyl)-methylthio)propionate (Step C, 0.122 g,0.35 mmol) in ethanol (5 ml) was added 1N NaOH (0.5 ml) at roomtemperature. The reaction mixture was stirred for 3 hours, acidifiedwith 1M HCl and concentrated in vacuo to give white solid which waspurified by flash chromatography on silica gel column(chloroform:methanol, 92.5:7.5 spiked with acetic acid) to provide thetitle compound as a white solid.

[0469]¹H NMR (270 MHz, CDCl₃): 2.4-2.6 (m, 4H); 3.7 (s, 2H); 5.1 (s,2H); 6.9 (d, 2H); 7.2-7.4 (m, 5H); 7.5 (t, 1H).

Example 4 Synthesis of 4-(4-(3-Fluorobenzyloxy)phenyl)-4-oxobutyric Acid

[0470]

[0471] Step A: Preparation of 4-(3-Fluorobenzyloxy)acetophenone:

[0472] Using the method of Example 1, Step A, using 3-Fluorobenzylbromide as the starting material, the title compound was obtained.

[0473]¹H NMR (270 MHz, CDCl₃): 2.5 (s, 3H); 5.1 (s, 2H); 7.0 (m, 3H);7.2-7.3 (t, 2H); 7.4 (m, 1H); 7.9 (d, 2H).

[0474] Step B: Preparation of Tert-Butyl4-(4-(3-fluorobenzyloxy)phenyl)-4-oxobutyrate:

[0475] Using the method of Example 1, Step B, the title compound wasobtained.

[0476]¹H NMR (270 MHz, CDCl₃): 1.4 (s, 9H); 2.7 (t, 2H); 3.2 (t, 2H);5.1 (s, 2H); 7.0 (m, 3H); 7.2 (t, 2H); 7.4 (m, 1H); 8.0 (d, 2H).

[0477] Step C: Preparation of4-(4-(3-Fluorobenzyloxy)phenyl)-4-oxobutyric Acid:

[0478] Using the method of Example 1, Step C, the title compound wasobtained.

[0479]¹H NMR (270 MHz, CDCl₃): 2.8 (t, 2H); 3.2 (t, 2H); 5.1 (s, 2H);6.9-7.1 (m, 3H); 7.2-7.3 (m, 2H); 7.4 (q, 1H); 7.9 (d, 2H).

Example 5 Synthesis of 4-(4-(4-Fluorobenzyloxy)phenyl)-4-oxobutyric Acid

[0480]

[0481] Step A: Preparation of 4-(4-Fluorobenzyloxy)acetophenone:

[0482] Using the method of Example 1, Step A, using 4-Fluorobenzylbromide as the starting material, the title compound was obtained.

[0483]¹H NMR (270 MHz, CDCl₃): 2.5 (s, 3H); 5.1 (s, 2H); 7.0 (d, 2H);7.1 (t, 2H); 7.4 (m, 2H); 7.9 (d, 2H).

[0484] Step B: Preparation of Tert-Butyl4-(4-(4-fluorobenzyloxy)phenyl)-4-oxobutyrate:

[0485] Using the method of Example 1, Step B, the title compound wasobtained

[0486]¹H NMR (270 MHz, CDCl₃): 1.4 (s, 9H); 2.8 (t, 2H); 3.2 (t, 2H);5.1 (s, 2H); 7.0 (m, 2H); 7.2 (t, 2H); 7.4 (m, 2H); 8.0 (d, 2H).

[0487] Step C: Preparation of4-(4-(4-Fluorobenzyloxy)phenyl)-4-oxobutyric Acid:

[0488] Using the method of Example 1, Step C, the title compound wasobtained.

[0489]¹H NMR (270 MHz, CDCl₃): 2.8 (t, 2H); 3.2 (t, 2H); 5.1 (s, 2H);6.9-7.1 (m, 2H); 7.2-7.3 (d, 2H); 7.4 (m, 2H); 7.9 (d, 2H).

Example 6 Synthesis of 4-(4-((2-Pyridinyl)-methoxy)phenyl)-4-oxobutyricAcid

[0490]

[0491] Step A: Preparation of 4-((2-Pyridinyl)-methoxy)acetophenone:

[0492] A solution of 4-Hydroxyacetophenone (1.99 g, 14.6 mmol) in dryDMF (5 ml) was added at room temperature to a suspension of NaH (60% inoil, 0.604 g) in dry DMF (20 ml). When evolution of hydrogen ceased,2-Picolyl chloride hydrochloride (2 g, 12.1 mmol) was added. Thereaction mixture was stirred at room temperature for 16 hours, quenchedwith sat aq. NH₄Cl and concentrated in vacuo. The crude residue wastaken in EtOAc and washed with water and brine. The aqueous layer waswashed twice with EtOAc. The combined organic layers were dried overNa₂SO₄, filtered and concentrated. The residue was purified by flashchromatography on silica gel column (hex:ethyl acetate, 1:1) to providethe title compound.

[0493]¹H NMR (270 MHz, CDCl₃): 2.5 (s, 3H); 5.2 (s, 2H); 7.0 (d, 2H);7.2 (m, 1H); 7.5 (d, 1H); 7.7 (t, 1H); 7.9 (d, 2H); 8.6 (s, 1H).

[0494] Step B: Preparation of Tert-Butyl4-(4-((2-pyridinyl)-methoxy)phenyl)-4-oxobutyrate:

[0495] To a stirred solution of 4-((2-Pyridinyl)-methoxy)acetophenone(Step A, 0.968 g, 3.6 mmol) in dry THF (16 ml) and DMPU (4 ml) was addeda solution of lithium bis(trimethylsilyl)amide (1.0M, 5 ml) at −60° C.under argon. After stirring for 10 minutes at −60° C., tert-Butylbromoacetate (2.64 g, 13.5 mmol) was added rapidly. The reaction mixturewas stirred for an additional 10 minutes and then warmed to roomtemperature for 4 hours. The crude mixture was taken in EtOAc and washedwith water and brine. The aqueous layer was extracted one more time withEtOAc. The combined organic layers were dried over Na₂SO₄, filtered,concentrated and purified by flash chromatography on silica gel column(hex:ethyl acetate, 2:1) to provide the title compound.

[0496]¹H NMR (270 MHz, CDCl₃): 1.4 (s, 9H); 2.7 (t, 2H); 3.2 (t, 2H);5.3 (s, 2H); 7.0 (d, 2H); 7.2 (m, 1H); 7.5 (d, 1H); 7.7 (t, 1H); 7.9 (d,2H); 8.6 (s, 1H).

[0497] Step C: Preparation of4-(4-((2-Pyridinyl)-methoxy)phenyl)-4-oxobutyric Acid:

[0498] A solution of tert-Butyl4-(4-((2-pyridinyl)-methoxy)phenyl)-4-oxobutyrate (Step C, 1.27 g, 4.2mmol) in dichloromethane (25 ml) was treated with trifluoroacetic acid(5 ml). The mixture was stirred at ambient temperature for 3 hours andconcentrated in vacuo. The purification was done by flash chromatographyon silica gel column (chloroform:methanol, 95:5 spiked with acetic acid)to provide the title compound as a white solid.

[0499]¹H NMR (270 MHz, CDCl₃:CD₃OD): 2.7 (t, 2H); 3.2 (t, 2H); 5.3 (s,2H); 7.0 (d, 2H); 7.3 (m, 1H); 7.5 (d, 1H); 7.9 (m, 3H); 8.6 (s, 1H).

Example 7 Synthesis of 4-(4-(Benzyloxy)phenyl)-4-oxobutyric Acid

[0500]

[0501] Step A: Preparation of 4-(Benzyloxy)acetophenone:

[0502] Using the method of Example 1, Step A, using Benzyl bromide asthe starting material, the title compound was obtained.

[0503]¹H NMR (270 MHz, CDCl₃): 2.5 (s, 3H); 5.1 (s, 2H); 7.0 (d, 2H);7.3-7.5 (m, 5H); 7.9 (d, 2H).

[0504] Step B: Preparation of Tert-Butyl4-(4-(benzyloxy)phenyl)-4-oxobutyrate:

[0505] Using the method of Example 1, Step B, the title compound wasobtained.

[0506]¹H NMR (270 MHz, CDCl₃): 1.4 (s, 9H); 2.6 (t, 2H); 3.2 (t, 2H);5.2 (s, 2H); 7.0 (d, 2H); 7.3-7.5 (m, 5H); 7.9 (d, 2H).

[0507] Step C: Preparation of 4-(4-(Benzyloxy)phenyl)-4-oxobutyric Acid:

[0508] Using the method of Example 1, Step C, the title compound wasobtained.

[0509]¹H NMR (270 MHz, CDCl₃): 2.8 (t, 2H); 3.2 (t, 2H); 5.1 (s, 2H);7.0 (d, 2H); 7.3-7.5 (m, 5H); 7.9 (d, 2H).

Example 8 Synthesis of 4-(4-(2,6-Difluorobenzyloxy)phenyl)-4-oxobutyricAcid

[0510]

[0511] Step A: Preparation of 4-(2,6-Difluorobenzyloxy)acetophenone:

[0512] A solution of 4-Hydroxyacetophenone (3.61 g, 26.5 mmol) in dryDMF (5 ml) was added at room temperature to a suspension of NaH (60% inoil, 1.21 g) in dry DMF (40 ml). When evolution of hydrogen ceased,2,6-Difluorobenzyl bromide (5 g, 24.1 mmol) was added drop wise. Thereaction mixture was stirred at room temperature for 6 hours, quenchedwith sat aq. NH₄Cl and concentrated in vacuo. The crude residue wastaken in EtOAc and washed with water and brine. The aqueous layer wasextracted one more time with EtOAc. The combined organic layers weredried over Na₂SO₄, filtered and concentrated. The residue was purifiedby flash chromatography on silica gel column (hex:ethyl acetate, 2:1) toprovide the title compound.

[0513]¹H NMR (270 MHz, CDCl₃): 2.5 (s, 3H); 5.2 (s, 2H); 6.9-7.0 (m,4H); 7.3-7.4 (m, 1H); 7.9 (d, 2H).

[0514] Step B: Preparation of Tert-Butyl4-(4-(2,6-difluorobenzyloxy)phenyl)-4-oxobutyrate:

[0515] To a stirred solution of 4-(2,6-Difluorobenzyloxy)acetophenone(Step A, 0.6 g, 22.8 mmol) in dry THF (60 ml) and DMPU (12 ml) was addeda solution of lithium bis(trimethylsilyl)amide (1.0M, 30 ml) at −60° C.under argon. After stirring for 10 minutes at −60° C., tert-Butylbromoacetate (8.97 g, 46 mmol) was added rapidly. The reaction mixturewas stirred for an additional 10 minutes and then warmed to roomtemperature for 4 hours. The crude mixture was taken in EtOAc and washedwith water and brine. The aqueous layer was extracted one more time withEtOAc. The combined organic layers were dried over Na₂SO₄, filtered,concentrated and purified by flash chromatography on a silica gel column(hex:ethyl acetate, 2:1) to provide the title compound as a white solid.

[0516]¹H NMR (270 MHz, CDCl₃): 1.4 (s, 9H); 2.6 (t, 2H); 3.2 (t, 2H);5.2 (s, 2H); 6.9-7.0 (m, 4H); 7.3-7.4 (m, 1H); 7.9 (d, 2H).

[0517] Step C: Preparation of4-(4-(2,6-Difluorobenzyloxy)phenyl)-4-oxobutyric Acid:

[0518] A solution of tert-Butyl4-(4-(2,6-difluorobenzyloxy)phenyl)-4-oxobutyrate (Step B, 4.76 g, 12.6mmol) in dichloromethane (40 ml) was treated with trifluoroacetic acid(20 ml). The mixture was stirred at ambient temperature for 3 hours andconcentrated in vacuo. The purification was done by flash chromatographyon silica gel column (chloroform:methanol, 95:5 spiked with acetic acid)to provide the title compound as a white powder.

[0519]¹H NMR (270 MHz, CDCl₃): 2.8 (t, 2H); 3.2 (t, 2H); 5.2 (s, 2H);6.9-7.0 (m, 4H); 7.4 (m, 1H); 7.9 (d, 2H).

Example 9 Synthesis of 4-(4-(2-Chlorobenzyloxy)phenyl)-4-oxobutyric Acid

[0520]

[0521] Step A: Preparation of 4-(2-Chlorobenzyloxy)acetophenone:

[0522] Using the method of Example 1, Step A, using 2-Chlorobenzylbromide as the starting material, the title compound was obtained.

[0523]¹H NMR (270 MHz, CDCl₃): 2.5 (s, 3H); 5.2 (s, 2H); 7.0 (d, 2H);7.2-7.5 (m, 4H); 7.9 (d, 2H).

[0524] Step B: Preparation of Tert-Butyl4-(4-(2-chlorobenzyloxy)phenyl)-4-oxobutyrate:

[0525] Using the method of Example 1, Step B, the title compound wasobtained.

[0526]¹H NMR (270 MHz, CDCl₃): 1.4 (s, 9H); 2.6 (t, 2H); 3.2 (t, 2H);5.2 (s, 2H); 7.0 (d, 2H); 7.2-7.5 (m, 4H); 7.9 (d, 2H).

[0527] Step C: Preparation of4-(4-(2-Chlorobenzyloxy)phenyl)-4-oxobutyric Acid:

[0528] Using the method of Example 1, Step C, the title compound wasobtained.

[0529]¹H NMR (270 MHz, CDCl₃:CD₃OD): 2.6 (t, 2H); 3.2 (t, 2H); 5.2 (s,2H); 7.0 (d, 2H); 7.2 (m, 2H); 7.3 (m, 1H); 7.4 (m, 1H); 7.9 (d, 2H).

Example 10 Synthesis of4-(4-(2-(2-Fluorophenyl)ethoxy)phenyl)-4-oxobutyric Acid

[0530]

[0531] Step A: Preparation of 4-(2-(2-fluorophenyl)ethoxy)acetophenone:

[0532] Using the method of Example 2, Step A, using 2-Fluorophenethylalcohol as the starting material, the title compound was obtained.

[0533]¹H NMR (270 MHz, CDCl₃): 2.3 (s, 3H); 2.9 (t, 2H); 4.2 (t, 2H);6.9 (d, 2H); 7.1 (m, 2H); 7.3 (m, 2H); 7.9 (d, 2H).

[0534] Step B: Preparation of Tert-Butyl4-(4-(2-(2-fluorophenyl)ethoxy)phenyl)-4-oxobutyrate:

[0535] Using the method of Example 2, Step B, using tert-Butylbromoacetate as the starting material, the title compound was obtained.

[0536]¹H NMR (270 MHz, CDCl₃): 1.4 (s, 9H); 2.6 (t, 2H); 3.2 (m, 4H);4.2 (t, 2H); 6.9 (d, 2H); 7.1 (m, 2H); 7.3 (t, 2H); 7.9 (d, 2H).

[0537] Step C: Preparation of4-(4-(2-(2-Fluorophenyl)ethoxy)phenyl)-4-oxobutyric Acid:

[0538] A solution of tert-Butyl4-(4-(2-(2-Fluorophenyl)ethoxy)phenyl)-4-oxobutyrate (Step 2, 1.2 g, 3.2mmol) in dichloromethane (25 ml) was treated with trifluoroacetic acid(10 ml). The reaction mixture was stirred at ambient temperature for 4hours and concentrated in vacuo. The purification was done by flashchromatography on silica gel column (chloroform:methanol, 95:5 spikedwith acetic acid) to provide the title compound as a white solid.

[0539]¹H NMR (270 MHz, CDCl₃): 2.8 (t, 2H); 3.3 (t, 2H); 4.2 (t, 2H);6.9 (d, 2H); 7.1 (m, 2H); 7.3 (t, 2H); 7.9 (d, 2H).

Example 11 Synthesis of Ethyl4-(4-(2-Fluorobenzyloxyl)phenyl)-4-oxobutyrate

[0540]

[0541] Step A: Preparation of 4-(4-(2-Fluorobenzyloxy)acetophenone:

[0542] Using the method of Example 1, Step A, the title compound wasobtained.

[0543]¹H NMR (270 MHz, CDCl₃): 2.5 (s, 3H); 5.2 (s, 2H); 6.9-7.1 (m,4H); 7.2-7.3 (m, 1H); 7.4 (t, 1H); 7.9 (d, 2H).

[0544] Step B: Preparation of Ethyl4-(4-(2-fluorobenzyloxy)phenyl)-4-oxobutyrate:

[0545] To a stirred solution of 4-(2-Fluorobenzyloxy)acetophenone (7.26g, 29.7 mmol) in dry THF (80 ml) and DMPU (16 ml) was added a solutionof lithium bis(trimethylsilyl)amide (1.0M, 35 ml) at −60° C. underargon. After stirring for 10 minutes at −6⁰° C., Ethyl bromoacetate(10.12 g, 60.5 mmol) was added rapidly. The reaction mixture was stirredfor an additional 10 minutes and then warmed to room temperature for 4hours. The crude mixture was taken in EtOAc and washed with water andbrine. The aqueous layer was extracted one more time with EtOAc. Thecombined organic layers were dried over Na₂SO₄, filtered, concentratedand purified by flash chromatography on a silica gel column (hex:ethylacetate, 4:1) to provide the title compound as a white powder.

[0546]¹H NMR (270 MHz, CDCl₃): 1.2 (t, 3H); 2.7 (t, 2H); 3.2 (t, 2H);4.2 (q, 2H); 5.1 (s, 2H); 6.9 (d, 2H); 7.2 (m, 2H); 7.4 (m, 1H); 7.5 (m,1H); 7.9 (d, 2H).

Example 12 Synthesis of 4-(4-(2-Methylbenzyloxy)phenyl)-4-oxobutyricAcid

[0547]

[0548] Step A: Preparation of 4-(2-Methylbenzyloxy)acetophenone:

[0549] Using the method of Example 1, Step A, using 2-Methylbenzylbromide as the starting material, the title compound was obtained.

[0550]¹H NMR (270 MHz, CDCl₃): 2.4 (s, 3H); 2.5 (s, 3H); 5.2 (s, 2H);6.9 (d, 2H); 7.2-7.3 (m, 3H); 7.4 (m, 1H); 7.9 (d, 2H).

[0551] Step B: Preparation of Tert-Butyl4-(4-(2-methylbenzyloxy)phenyl)-4-oxobutyrate:

[0552] Using the method of Example 1, Step B, the title compound wasobtained.

[0553]¹H NMR (270 MHz, CDCl₃): 1.5 (s, 9H); 2.4 (s, 3H); 2.6 (t, 2H);3.2 (t, 2H); 5.2 (s, 2H); 6.9 (d, 2H); 7.2-7.3 (m, 3H); 7.4 (m, 1H); 7.9(d, 2H).

[0554] Step C: Preparation of4-(4-(2-Methylbenzyloxy)phenyl)-4-oxobutyric Acid:

[0555] Using the method of Example 1, Step C, the title compound wasobtained.

[0556]¹H NMR (270 MHz, CDCl₃): 2.4 (s, 3H); 2.8 (t, 2H); 3.2 (t, 2H);5.1 (s, 2H); 6.9 (d, 2H); 7.2-7.3 (m, 3H); 7.4 (m, 1H); 7.9 (d, 2H).

Example 13 Synthesis of4-[4-(2-(N-(2-fluorobenzyl)-N-methylamino)ethoxy)phenyl]-4-oxobutyricAcid

[0557]

[0558] Step A: Preparation of 2-Fluorobenzyl Methanesulfonate:

[0559] To a solution of 2-Fluorobenzyl alcohol (10 g, 79.28 mmol) in drydichloromethane (200 ml) was added triethylamine (12.03 g, 118.9 mmol)under argon at room temperature. Methanesulfonyl chloride (10.71 g, 93.5mmol) was added to the above reaction mixture at 0° C., and stirring wascontinued for another 3 hours. Water (100 ml) was added to the reactionmixture and the mixture was extracted twice with dichloromethane. Thecombined organic layers were washed with water and brine. The reactionmixture was dried over Na₂SO₄, filtered and concentrated to give thetitle compound as an yellow oil which was used without furtherpurification.

[0560]¹H NMR (270 MHz, CDCl₃): 1.3 (t, 3H); 2.4-2.6 (m, 4H); 5.25 (s,2H); 6.9-7.5 (m, 4H).

[0561] Step B: Preparation of2-(N-(2-fluorobenzyl)-N-methylamino)-ethanol:

[0562] A mix of 2-Fluorobenzyl methanesulfonate (Step A, 5 g, 24.5 mmol)and 2-(Methylamino)-ethanol (18.4 g, 244.9 mmol) was heated under argonat 120° C. with stirring for 7 hours. The mixture was cooled to roomtemperature and concentrated. The crude residue was purified by flashchromatography on silica gel column (chloroform:methanol, 90:10 spikedwith triethylamine) to provide the title compound.

[0563]¹H NMR (270 MHz, CDCl₃): 2.3 (s, 3H); 2.6 (m, 2H); 3.6 (m, 4H);6.9-7.5 (m, 4H).

[0564] Step C: Preparation of 2-(N-(2-fluorobenzyl)-N-methylamino)-ethylChloride:

[0565] To a solution of 2-(N-(2-fluorobenzyl)-N-methylamino)-ethanol(Step. B, 7.51 g, 41 mmol) in dry toluene (50 ml) was added thionylchloride (16 ml). The reaction mixture was stirred at room temperaturefor 16 hours and concentrated. The crude mixture was diluted withchloroform and washed with aq NaHCO₃, water and brine. The organic layerwas dried over Na₂SO₄, filtered and concentrated to provide the titlecompound which was used without further purification.

[0566]¹H NMR (270 MHz, CDCl₃): 2.3 (s, 3H); 2.8 (t, 2H); 3.6 (t, 2H);3.7. (s, 2H); 7.0-7.15 (m, 2H); 7.25 (m, 1H), 7.4 (t, 1H).

[0567] Step D: Preparation of4-(2-(N-(2-fluorobenzyl)-N-methylamino)ethoxy)acetophenone:

[0568] To a solution of 2-(N-(2-fluorobenzyl)-N-methylamino)-ethylchloride (Step C, 7.48 g, 37 mmol) and 4-Hydroxyacetophenone (10.07 g,74 mmol) in dry DMF (10 ml) was added K₂CO₃ (7.77 g, 56.2 mmol). Themixture was heated at 80° C. for 6 hours, cooled, quenched with waterand extracted twice with EtOAc. The combined organic layers were driedover Na₂SO₄, filtered and concentrated. The crude residue was purifiedby flash chromatography on silica gel column (hex:ethyl acetate, 2:1) toprovide the title compound as a light yellow oil.

[0569]¹H NMR (270 MHz, CDCl₃): 2.35 (s, 3H); 2.4 (s, 3H); 2.8 (t, 2H);3.7 (s, 2H); 4.2 (t, 2H); 6.9 (d, 2H); 7.0-7.15 (m, 2H); 7.25 (m, 1H),7.4 (t, 1H); 7.9 (d, 2H).

[0570] Step E: Preparation of Tert-Butyl4-[4-(2-(N-(2-fluorobenzyl)-N-methylamino)ethoxy)phenyl]-4-oxobutyrate:

[0571] Lithium bis(trimethylsilyl)amide (1.0M, 20 ml) was added slowlyover 10 minutes to a stirred solution of4-(2-(N-(2-fluorobenzyl)-N-methylamino)ethoxy)acetophenone (Step D, 4.91g, 16.3 mmol) in dry THF (60 ml) and DMPU (15 ml) at −65° C. underargon. After 15 minutes of stirring, tert-Butyl bromoacetate (6.35 g,32.6 mmol) was added rapidly. The stirring continued for an additional10 minutes at −65° C. and then reaction was warmed to room temperaturefor 2 hours, quenched with water and extracted twice with EtOAc. Thecombined organic layers were purified by flash chromatography on silicagel column (hex:ethyl acetate, 1:1) to provide the title compound.

[0572]¹H NMR (270 MHz, CDCl₃): 1.5 (s, 9H); 2.4 (s, 3H); 2.6 (t, 2H);2.8 (t, 2H); 3.2 (t, 2H) 3.7 (br, 2H); 4.2 (br, 2H); 6.9 (d, 2H);7.0-7.15 (m, 2H); 7.25 (m, 1H), 7.4 (t, 1H); 7.9 (d, 2H).

[0573] Step F: Preparation of4-[4-(2-(N-(2-fluorobenzyl)-N-methylamino)ethoxy)phenyl]-4-oxobutyricAcid:

[0574] A solution of tert-Butyl4-[4-(2-(N-(2-fluorobenzyl)-N-methylamine)ethoxy)phenyl]-4-oxobutyrate(Step E, 2.23 g, 5.3 mol) in dichloromethane (20 ml) was treated withtrifluoroacetic acid (10 ml). The reaction mixture was stirred atambient temperature for 2 hours, and concentrated in vacuo. Thepurification was done by flash chromatography on silica gel column(chloroform:methanol, 92.5:7.5-90:10 spiked with acetic acid) to providethe title compound.

[0575]¹H NMR (270 MHz, CDCl₃:CD₃OD): 2.5 (t, 2H); 2.6 (s, 3H); 3.0 (t,2H); 3.4 (t, 2H); 4.2-4.5 (m, 4H); 6.9 (d, 2H); 7.0-7.15 (m, 2H); 7.3(m, 1H), 7.5 (t, 1H); 7.9 (d, 2H).

Example 14 Synthesis of 4-(3-(2-Methylbenzyloxy)phenyl)-4-oxobutyricAcid

[0576]

[0577] Step A: Preparation of 3-(2-Methylbenzyloxy)acetophenone:

[0578] Using the method of Example 12, Step A, using3-Hydroxyacetophenone as the starting material, the title compound wasobtained.

[0579]¹H NMR (270 MHz, CDCl₃): 2.3 (s, 3H); 2.5 (s, 3H); 5.1 (s, 2H);7.2-7.3 (m, 4H); 7.4 (m, 2H); 7.6 (m, 2H).

[0580] Step B: Preparation of Tert-Butyl4-(3-(2-methylbenzyloxy)phenyl)-4-oxobutyrate:

[0581] Using the method of Example 1, Step B, the title compound wasobtained.

[0582]¹H NMR (270 MHz, CDCl₃): 1.5 (s, 9H); 2.4 (s, 3H); 2.6 (t, 2H);3.2 (t, 2H); 5.2 (s, 2H); 7.2-7.3 (m, 4H); 7.4 (m, 2H); 7.6 (m, 2H).

[0583] Step C: Preparation of4-(3-(2-Methylbenzyloxy)phenyl)-4-oxobutyric Acid:

[0584] Using the method of Example 1, Step C, the title compound wasobtained

[0585]¹H NMR (270 MHz, CDCl₃): 2.4 (s, 3H); 2.8 (t, 2H); 3.3 (t, 2H);5.1 (s, 2H); 7.2-7.3 (m, 4H); 7.4 (m, 2H); 7.6 (m, 2H).

Example 15 Synthesis of Ethyl4-(3-(2-fluorobenzyloxyl)phenyl)-4-oxobutyrate

[0586]

[0587] Step A: Preparation of 3-(2-Fluorobenzyloxy)acetophenone:

[0588] Using the method of Example 1, Step A, using3-Hydroxyacetophenone as the starting material, the title compound wasobtained.

[0589]¹H NMR (270 MHz, CDCl₃): 2.5 (s, 3H); 5.2 (s, 2H); 7.1 (m, 4H);7.3 (m, 2H); 7.6 (m, 2H)

[0590] Step B: Preparation of Ethyl4-(3-(2-fluorobenzyloxy)phenyl)-4-oxobutyrate:

[0591] Using the method of Example 11, Step B, the title compound wasobtained.

[0592]¹H NMR (270 MHz, CDCl₃): 1.3 (s, 9H); 2.8 (t, 2H); 3.3 (t, 2H);5.1 (s, 2H); 7.1 (t, 2H); 7.2 (d, 2H); 7.4 (m, 1H); 7.5 (t, 1H); 7.6 (d,2H).

Example 16 Synthesis of Ethyl4-(4-(2-methylbenzyloxyl)phenyl)-4-oxobutyrate

[0593]

[0594] Step A: Preparation of 4-(2-Methylbenzyloxy)acetophenone:

[0595] Using the method of Example 12, Step A, the title compound wasobtained.

[0596]¹H NMR (270 MHz, CDCl₃): 2.4 (s, 3H); 2.5 (s, 3H); 5.2 (s, 2H);6.9 (d, 2H); 7.2-7.3 (m, 3H); 7.4 (m, 1H); 8.0 (d, 2H).

[0597] Step B: Preparation of Ethyl4-(4-(2-methylbenzyloxy)phenyl)-4-oxobutyrate:

[0598] Using the method of Example 11, Step B, the title compound wasobtained.

[0599]¹H NMR (270 MHz, CDCl₃): 1.2 (t, 3H); 2.4 (s, 3H); 2.7 (t, 2H);3.2 (t, 2H); 4.2 (q, 2H); 5.1 (s, 2H); 7.0 (d, 2H); 7.2-7.3 (m, 3H); 7.4(m, 1H); 8.0 (d, 2H).

Example 17 Synthesis of Ethyl4-(4-(2,6-difluorobenzyloxyl)phenyl)-4-oxobutyrate

[0600]

[0601] Step A: Preparation of 4-(2,6-Difluorobenzyloxy)acetophenone:

[0602] Using the method of Example 8, Step A, the title compound wasobtained

[0603]¹H NMR (270 MHz, CDCl₃): 2.5 (s, 3H); 5.2 (s, 2H); 6.9-7.0 (m,4H); 7.3-7.4 (m, 1H); 7.9 (d, 2H).

[0604] Step B: Preparation of Ethyl4-(4-(2,6-Difluorobenzyloxy)phenyl)-4-oxobutyrate:

[0605] To a stirred solution of 4-(2,6-Difluorobenzyloxy)acetophenone(Step A, 0.6 g, 22.8 mmol) in dry THF (60 ml) and DMPU (12 ml) was addeda solution of lithium bis(trimethylsilyl)amide (1.0M, 30 ml) at −60° C.under argon. After stirring for 10 minutes at −60° C., Ethylbromoacetate (7.61 g, 45.6 mmol) was added rapidly. The reaction mixturewas stirred for an additional 10 minutes and then warmed to roomtemperature for 4 hours. The crude mixture was taken in EtOAc and washedwith water and brine. The aqueous layer was extracted one more time withEtOAc. The combined organic layers were dried over Na₂SO₄, filtered,concentrated and purified by flash chromatography on silica gel column(hex:ethyl acetate, 4:1) to provide the title compound as a white solid.

[0606]¹H NMR (270 MHz, CDCl₃): 1.3 (t, 3H); 2.8 (t, 3H); 3.2 (t, 2H);4.1 (q, 2H); 5.2 (s, 2H); 6.9-7.0 (m, 4H); 7.3-7.4 (m, 1H); 7.9 (d, 2H).

Example 18 Synthesis of 4-(4-(2-(2-Thienyl)ethoxy)phenyl)-4-oxobutyricAcid

[0607]

[0608] Step A: Preparation of 4-(2-(2-Thienyl)ethoxy)acetophenone:

[0609] Using the method of Example 2, Step A, using 2-(2-Thienyl)ethanolas the starting material and purification by flash chromatography onsilica gel column (hex:ethylacetate, 3:1), the title compound wasobtained.

[0610]¹H NMR (270 MHz, CDCl₃): 2.5 (s, 3H); 3.3 (t, 2H); 4.2 (t, 2H);6.9-7.1 (m, 4H); 7.2 (d, 1H); 7.9 (d, 2H).

[0611] Step B: Preparation of Ethyl4-(4-(2-(2-thienyl)ethoxy)phenyl)-4-oxobutyrate:

[0612] Using the method of Example 2, Step B, the title compound wasobtained.

[0613]¹H NMR (270 MHz, CDCl₃): 1.3 (t, 3H); 2.8 (t, 2H); 3.3 (m, 4H);4.1 (q, 2H); 4.2 (t, 2H); 6.9-7.1 (m, 4H); 7.2 (d, 1H); 7.9 (d, 2H).

[0614] Step C: Preparation of4-(4-(2-(2-Thienyl)ethoxy)phenyl)-4-oxobutyric Acid:

[0615] Using the method of Example 2, Step C, the title compound wasobtained

[0616]¹H NMR (270 MHz, CDCl₃): 2.8 (t, 2H); 3.3 (m, 4H); 4.2 (t, 2H);6.9-7.1 (m, 4H); 7.2 (d, 1H); 7.9 (d, 2H).

Example 19 Synthesis of 4-(2,6-Difluorophenyl)-4-oxobutyric Acid

[0617]

[0618] Step A: Preparation of Tert-Butyl4-(2,6-difluorophenyl)-4-oxobutyrate:

[0619] To a stirred solution of 2,6-Difluoroacetophenone (5 g, 32 mmol)in dry THF (40 ml) and DMPU (8 ml) was added a solution of lithiumbis(trimethylsilyl)amide (1.0M, 45 ml) at 60° C. under argon. Afterstirring for 10 minutes at −60° C., tert-Butyl bromoacetate (6.99 g,35.8 mmol) was added rapidly. The reaction mixture was stirred for anadditional 10 minutes and then warmed to room temperature for 4 hours.The crude mixture was taken in EtOAc and washed with water and brine.The aqueous layer was extracted one more time with EtOAc. The combinedorganic layers were dried over Na₂SO₄, filtered, concentrated andpurified by flash chromatography on a silica gel column (hex:ethylacetate, 2:1) to provide the title compound.

[0620]¹H NMR (270 MHz, CDCl₃): 1.4 (s, 9H); 2.8 (t, 2H); 3.2 (t, 2H);6.9-7.0 (m, 2H); 7.4 (m, 1H).

[0621] Step B: Preparation of Compound AS:

[0622] A solution of tert-Butyl 4-(2,6-difluorophenyl)-4-oxobutyrate(Step A, 9.52 g, 35.2 mmol) in dichloromethane (30 ml) was treated withtrifluoroacetic acid (20 ml). The mixture was stirred at ambienttemperature for 3 hours and concentrated. The purification was done byflash chromatography on silica gel column (chloroform:methanol, 95:5spiked with acetic acid) to provide the title compound as a white solid.

[0623]¹H NMR (270 MHz, CDCl₃): 2.8 (t, 2H); 3.2 (t, 2H); 6.9-7.0 (m,214); 7.4 (m, 1H).

Example 20 Synthesis of 4-(4-(2,5-Dimethylbenzyloxy)phenyl)-4-oxobutyricAcid

[0624]

[0625] Step A: Preparation of 4-(2,5-Dimethylbenzyloxy)acetophenone:

[0626] Using the method of Example 8, Step A, using 2,5-Dimethylbenzylchloride as the starting material, the title compound was obtained.

[0627]¹H NMR (270 MHz, CDCl₃): 2.3 (s, 3H); 2.5 (s, 3H); 5.1 (s, 2H);6.9-7.2 (m, 5H); 7.9 (d, 2H).

[0628] Step B: Preparation of Ethyl4-(4-(2,5-dimethylbenzyloxy)phenyl)-4-oxobutyrate:

[0629] Using the method of Example 17, Step B, the title compound wasobtained.

[0630]¹H NMR (270 MHz, CDCl₃): 1.2 (s, 3H); 2.3 (s, 6H); 2.8 (t, 2H);3.2 (t, 2H); 4.4 (q, 2H); 5.1 (s, 2H); 7.0 (d, 2H); 7.2-7.3 (m, 3H); 7.9(d, 2H).

[0631] Step C: Preparation of4-(4-(2,5-Dimethylbenzyloxy)phenyl)-4-oxobutyric Acid:

[0632] To a solution of Ethyl4-(4-(2,5-dimethylbenzyloxy)phenyl)-4-oxobutyrate (Step B, 2.62 g, 7.7mmol) in abs ethanol (30 ml) was added 1N NaOH (10 ml) at roomtemperature. The reaction mixture was stirred for 3 hours and thenacidified with 1M HCl. The occuring white precipitate was filtered,washed with water and dried under vacuum to provide the title compoundas a white solid.

[0633]¹H NMR (270 MHz, CDCl₃): 2.3 (s, 6H); 2.8 (t, 2H); 3.2 (t, 2H);5.1 (s, 2H); 7.0 (d, 2H); 7.2-7.3 (m, 3H); 8.0 (d, 2H).

Example 21 Synthesis of 4-(4-(2,5-Difluorobenzyloxy)phenyl)-4-oxobutyricAcid

[0634]

[0635] Step A: Preparation of 4-(2,5-Difluorobenzyloxy)acetophenone:

[0636] Using the method of Example 8, Step A, using 2,5-Difluorolbenzylbromide as the starting material, the title compound was obtained.

[0637]¹H NMR (270 MHz, CDCl₃): 2.5 (s, 3H); 5.1 (s, 2H); 6.9-7.0 (m,3H); 7.2 (m, 2H); 8.0 (d, 2H).

[0638] Step B: Preparation of Ethyl4-(4-(2,5-difluorobenzyloxy)phenyl)-4-oxobutyrate:

[0639] Using the method of Example 17, Step B, the title compound wasobtained.

[0640]¹H NMR (270 MHz, CDCl₃): 1.2 (s, 3H); 2.8 (t, 2H); 3.2 (t, 2H);4.4 (q, 2H); 5.1 (s, 2H); 6.9-7.0 (m, 3H); 7.2 (m, 2H); 8.0 (d, 2H).

[0641] Step C: Preparation of4-(4-(2,5-Difluorobenzyloxy)phenyl)-4-oxobutyric Acid:

[0642] To a solution of Ethyl4-(4-(2,5-Difluorobenzyloxy)phenyl)-4-oxobutyrate (Step B, 16.51 g, 47.4mmol) in abs ethanol (100 ml) was added 1N NaOH (40 ml) at roomtemperature. The reaction mixture was stirred for 3 hours, acidifiedwith 1M HCl and concentrated in vacuo. The crude mixture was taken inchloroform and washed with water. The aqueous layer was washed one moretime with chloroform. The combined organic layers were dried overNa₂SO₄, filtered and concentrated. The purification was done by flashchromatography on silica gel column (chloroform:methanol, 95:5 spikedwith acetic acid) to provide the title compound as a white solid.

[0643]¹H NMR (270 MHz, CDCl₃): 2.8 (t, 2H); 3.3 (t, 2H); 5.1 (s, 2H);6.9-7.0 (m, 3H); 7.2 (m, 2H); 8.0 (d, 2H).

Example 22 Synthesis of 4-(4-(2,4-Difluorobenzyloxy)phenyl)-4-oxobutyricAcid

[0644]

[0645] Step A: Preparation of 4-(2,4-Difluorobenzyloxy)acetophenone:

[0646] Using the method of Example 8, Step A, using 2,4-Difluorolbenzylbromide as the starting material, the title compound was obtained.

[0647]¹H NMR (270 MHz, CDCl₃): 2.5 (s, 3H); 5.1 (s, 2H); 6.9-7.0 (m,2H); 7.1 (d, 2H); 7.4 (m, 1H); 8.0 (d, 2H).

[0648] Step B: Preparation of Ethyl4-(4-(2,4-difluorobenzyloxy)phenyl)-4-oxobutyrate:

[0649] Using the method of Example 17, Step B, the title compound wasobtained.

[0650]¹H NMR (270 MHz, CDCl₃): 1.2 (s, 3H); 2.8 (t, 2H); 3.2 (t, 2H);4.4 (q, 2H); 5.1 (s, 2H); 6.9-7.0 (m, 2H); 7.1 (d, 2H); 7.4 (m, 1H); 8.0(d, 2H).

[0651] Step C: Preparation of4-(4-(2,4-Difluorobenzyloxy)phenyl)-4-oxobutyric Acid:

[0652] Using the method of Example 21, Step C, the title compound wasobtained.

[0653]¹H NMR (270 MHz, CDCl₃): 2.8 (t, 2H); 3.2 (t, 2H); 5.1 (s, 2H);6.9-7.0 (m, 2H); 7.1 (d, 2H); 7.4 (m, 1H); 8.0 (d, 2H).

Example 23 Synthesis of 4-(3-(2,6-Difluorobenzyloxy)phenyl)-4-oxobutyricAcid

[0654]

[0655] Step A: Preparation of 3-(2,6-Difluorobenzyloxy)acetophenone:

[0656] Using the method of Example 8, Step A, using3-Hydroxyacetophenone as the starting material, the title compound wasobtained.

[0657]¹H NMR (270 MHz, CDCl₃): 2.5 (s, 3H); 5.2 (s, 2H); 6.9-7.0 (m,2H); 7.2 (m, 1H); 7.4 (m, 2H); 7.9 (d, 2H).

[0658] Step B: Preparation of Ethyl4-(3-(2,6-difluorobenzyloxy)phenyl)-4-oxobutyrate:

[0659] Using the method of Example 17, Step B, the title compound wasobtained.

[0660]¹H NMR (270 MHz, CDCl₃): 1.2 (s, 3H); 2.8 (t, 2H); 3.2 (t, 2H);4.4 (q, 2H); 5.1 (s, 2H); 6.9-7.0 (m, 2H); 7.2 (m, 1H); 7.4 (m, 2H); 7.9(d, 2H).

[0661] Step C: Preparation of4-(3-(2,6-difluorobenzyloxy)phenyl)-4-oxobutyric Acid:

[0662] Using the method of Example 21, Step C, the title compound wasobtained.

[0663]¹H NMR (270 MHz, CDCl₃): 2.8 (t, 2H); 3.2 (t, 2H); 5.1 (s, 2H);6.9-7.0 (m, 2H); 7.2 (m, 1H); 7.4 (m, 2H); 7.9 (d, 2H).

Example 24 Synthesis of 4-(4-((Cyclopropyl)-methoxy)phenyl)-4-oxobutyricAcid

[0664]

[0665] Step A: Preparation of 4-((Cyclopropyl)-methoxy)acetophenone:

[0666] Using the method of Example 8, Step A, using Cyclopropylmethylbromide as the starting material, the title compound was obtained.

[0667]¹H NMR (270 MHz, CDCl₃): 0.4 (m, 2H); 0.6 (m, 2H); 1.2 (m, 1H);2.5 (s, 3H); 3.8 (d, 2H); 6.9 (d, 2H); 7.9 (d, 2H).

[0668] Step B: Preparation of Tert-Butyl4-(4-((cyclopropyl)-methoxy)phenyl)-4-oxobutyrate:

[0669] Using the method of Example 8, Step B, the title compound wasobtained.

[0670]¹H NMR (270 MHz, CDCl₃): 0.4 (m, 2H); 0.6 (m, 2H); 1.2 (m, 1H);1.4 (s, 9H); 2.6 (t, 2H); 3.2 (t, 2H); 3.8 (d, 2H); 6.9 (d, 2H); 7.9 (d,2H).

[0671] Step C: Preparation of4-(4-((Cyclopropyl)-methoxy)phenyl)-4-oxobutyric Acid:

[0672] Using the method of Example 8, Step C, the title compound wasobtained.

[0673]¹H NMR (270 MHz, CDCl₃): 0.4 (m, 2H); 0.6 (m, 2H); 1.2 (m, 1H);2.8 (t, 2H); 3.2 (t, 2H); 3.8 (d, 2H); 6.9 (d, 2H); 7.9 (d, 2H).

Example 25 Synthesis of4-(4-(2-Trifluoromethylbenzyloxy)phenyl)-4-oxobutyric Acid

[0674]

[0675] Step A: Preparation of4-(2-Trifluoromethylbenzyloxy)acetophenone:

[0676] Using the method of Example 8, Step A, using2-(Trifluoromethyl)benzyl bromide as the starting material, the titlecompound was obtained.

[0677]¹H NMR (270 MHz, CDCl₃): 2.5 (s, 3H); 5.3 (s, 2H); 6.9 (d, 2H);7.4 (t, 1H); 7.6 (t, 1H); 7.7 (d, 2H); 7.9 (d, 2H).

[0678] Step B: Preparation of Tert-Butyl4-(4-(2-trifluoromethylbenzyloxy)phenyl)-4-oxobutyrate:

[0679] Using the method of Example 8, Step B, the title compound wasobtained.

[0680]¹H NMR (270 MHz, CDCl₃): 1.4 (s, 9H); 2.7 (t, 2H); 3.2 (t, 2H);5.3 (s, 2H); 6.9 (d, 2H); 7.4 (t, 1H); 7.6 (t, 1H); 7.7 (d, 2H); 7.9 (d,2H).

[0681] Step C: Preparation of4-(4-(2-Trifluoromethylbenzyloxy)phenyl)-4-oxobutyric Acid:

[0682] Using the method of Example 8, Step C, the title compound wasobtained.

[0683]¹H NMR (270 MHz, CDCl₃): 2.8 (t, 2H); 3.2 (t, 2H); 5.3 (s, 2H);6.9 (d, 2H); 7.4 (t, 1H); 7.6 (t, 1H); 7.7 (t, 2H); 7.9 (d, 2H).

Example 26 Synthesis of3-[(4-(2,6-Difluorobenzyloxy)phenyl)-methylthio]propionic Acid

[0684]

[0685] Step A: Preparation of 4-Hydroxybenzyl Bromide:

[0686] Using the method of Example 3, Step A, the title compound wasobtained which was used without further purification.

[0687] Step B: Preparation of Ethyl3-[(4-hydroxyphenyl)-methylthio]propionate:

[0688] Using the method of Example 3, Step B, the title compound wasobtained.

[0689]¹H NMR (270 MHz, CDCl₃): 1.2 (t, 3H); 2.4-2.6 (m, 4H); 3.6 (s,2H); 4.1 (q, 2H); 6.7 (d, 2H); 7.2 (d, 2H).

[0690] Step C: Preparation of Ethyl3-[(4-(2,6-difluorobenzyloxy)phenyl)methylthio]propionate:

[0691] Using the method of Example 3, Step C, using 2,6-Difluorobenzylbromide as the starting material, the title compound was obtained.

[0692]¹H NMR (270 MHz, CDCl₃): 1.2 (t, 3H); 2.4-2.6 (m, 4H); 3.6 (s,2H); 4.2 (q, 2H); 5.15 (s, 2H); 6.9 (d, 4H); 7.2-7.4 (m, 3H).

[0693] Step D: Preparation of3-[(4-(2,6-Difluorobenzyloxy)phenyl)-methylthio]propionic Acid:

[0694] Using the method of Example 3, Step D, the title compound wasobtained.

[0695]¹H NMR (270 MHz, CDCl₃): 2.5-2.6 (m, 4H); 3.7 (s, 2H); 5.1 (s,2H); 6.9-7.0 (m, 4H); 7.2-7.4 (m, 3H).

Example 27 Synthesis of 4-(2-(2,6-Difluorobenzyloxy)phenyl)-4-oxobutyricAcid

[0696]

[0697] Step A: Preparation of 2-(2,6-Difluorobenzyloxy)acetophenone:

[0698] Using the method of Example 8, Step A, using2-Hydroxyacetophenone as the starting material, the title compound wasobtained.

[0699]¹H NMR (270 MHz, CDCl₃): 2.5 (s, 3H); 5.2 (s, 2H); 6.9-7.0 (m,3H); 7.1 (d, 1H); 7.4 (m, 1H); 7.5 (t, 1H); 7.8 (d, 1H).

[0700] Step B: Preparation of Ethyl4-(2-(2,6-difluorobenzyloxy)phenyl)-4-oxobutyrate:

[0701] Using the method of Example 17, Step B, the title compound wasobtained.

[0702]¹H NMR (270 MHz, CDCl₃): 1.2 (s, 3H); 2.6 (t, 2H); 3.2 (t, 2H);4.1 (q, 2H); 5.2 (s, 2H); 6.9-7.0 (m, 3H); 7.1 (d, 1H); 7.4 (m, 1H); 7.5(t, 1H); 7.8 (d, 1H).

[0703] Step C: Preparation of4-(2-(2,6-Difluorobenzyloxy)phenyl)-4-oxobutyric Acid:

[0704] Using the method of Example 21, Step C, the title compound wasobtained.

[0705]¹H NMR (270 MHz, CDCl₃): 2.6 (t, 2H); 3.2 (t, 2H); 5.2 (s, 2H);6.9-7.0 (m, 3H); 7.1 (d, 1H); 7.4 (m, 1H); 7.5 (t, 1H); 7.8 (d, 1H).

Example 28 Synthesis of Ethyl4-(4-(2,6-difluorobenzyloxy)phenyl)-3-oxobutyrate

[0706]

[0707] Step A: Preparation of Ethyl 4-hydroxybenzylate:

[0708] To a stirred solution of 4-Hydroxybenzyl alcohol (4 g, 26.28mmol) in dry DMF (15 ml), pyridine (1 ml) andN,N-Dicyclohexylcarbodiimide (6.50 g, 31.5 mmol) was added abs EtOH(3.26 g, 78.84 mmol). The reaction mixture was stirred for 18 hours atroom temperature and then filtered. The filtrate was concentrated underreduced pressure and purified by flash chromatography on silica gelcolumn (hex:ethyl acetate, 2:1) to provide the title compound.

[0709]¹H NMR (270 MHz, CDCl₃): 1.2 (t, 3H); 3.5 (s, 2H); 4.1 (q, 2H);6.7 (d, 2H); 7.1 (d, 2H).

[0710] Step B: Preparation of Ethyl 4-(2,6-difluorobenzyloxy)benzylate:

[0711] To a solution of NaH (60% dispersed in oil, 0.393 g, 9.8 mmol) indry DMF (20 ml) was added Ethyl 4-hydroxybenzylate (Step A, 1.59 g, 8.8mmol). When the evolution of hydrogen ceased, 2,6-Difluorobenzyl bromide(1.64 g, 7.9 mmol) was added. The reaction mixture was stirred for 4hours at room temperature, quenched with sat. NH₄Cl, and concentrated invacuo. The residue was taken in EtOAc and washed twice with water andbrine. The organic layer was dried over Na₂SO₄, filtered, concentratedand purified by flash chromatography on silica gel column (hex:ethylacetate, 2:1) to provide the title compound.

[0712]¹H NMR (270 MHz, CDCl₃): 1.2 (t, 3H); 3.5 (s, 2H); 4.1 (q, 2H);5.1 (s, 2H); 6.9 (m, 4H); 7.2-7.4 (m, 3H).

[0713] Step C: Preparation of 4-(2,6-Difluorobenzyloxy)benzylic Acid:

[0714] To a stirred solution of Ethyl 4-(2,6-difluorobenzyloxy)benzylate(Step B, 2.14 g, 6.9 mmol) in abs EtOH (30 ml) was added 1N NaOH (10 ml)at room temperature. The reaction mixture was stirred for 3 hours,acidified by 1M HCl and filtered. The white precipitate was washed withwater and dried under high vacuum to provide the title compound.

[0715]¹H NMR (270 MHz, CDCl₃): 3.6 (s, 2H); 5.1 (s, 2H); 6.9 (m, 4H);7.2-7.4 (m, 3H).

[0716] Step D: preparation of 4-(2,6-Difluorobenzyloxy)benzylcarbonylChloride:

[0717] Thionyl chloride (10 ml) was added to 4-(2,6Difluorobenzyloxy)benzylic acid (Step C, 1.61 g, 5.79 mmol). Thereaction mixture was refluxed for 3 hours and concentrated in vacuo toprovide light yellow oil which was used without further purification.

[0718] Step E: Ethyl 4-(4-(2,6-difluorobenzyloxy)phenyl)-3-oxobutyrate:

[0719] To a solution of Meldrum's acid (0.846 g, 5.8 mmol) indichloromethane (5 ml) was added pyridine (2 ml) over a period of 10minutes at 0° C. To this solution was added4-(2,6-Difluorobenzyloxy)benzylcarbonyl chloride (Step D, 1.71 g, 5.7mmol) in dichloromethane (5 ml), which resulted in an orange solution.The dark orange solution was stirred for 1 hour at 0° C., allowed towarm to room temperature and stirred for an additional hour. Thereaction mixture was diluted with dichloromethane and poured onto 2M HCland ice. The phases were separated and the aqueous phase was extractedtwice with dichloromethane. The combined organic layers were washedtwice with 2M HCl and brine, dried over Na₂SO₄, filtered andconcentrated to a solid. The solid was suspended in abs EtOH (15 ml) andrefluxed for 2.5 hours. The solvent was removed in vacuo to give a darkoil. The residue was purified by flash chromatography on silica gelcolumn (hex:ethyl acetate, 2:1) to provide the title compound as a whitesolid.

[0720]¹H NMR (270 MHz, CDCl₃): 1.2 (t, 3H); 3.4 (s, 2H); 3.7 (s, 2H);4.2 (q, 2H); 5.1 (s, 2H); 6.9 (m, 4H); 7.1 (d, 2H); 7.3 (m, 1H).

Example 29 Synthesis of3-(2-(4-(2,6-Difluorobenzyloxy)phenyl)-2-oxoethyl)thio-1H-1,2,4-triazole

[0721]

[0722] Step A: Preparation of 4-(2,6-Difluorobenzyloxy)acetophenone:

[0723] Using the method of Example 8, Step A, the title compound wasobtained.

[0724]¹H NMR (270 MHz, CDCl₃): 2.5 (s, 3H); 5.2 (s, 2H); 6.9-7.0 (m,4H); 7.3-7.4 (m, 1H); 7.9 (d, 2H).

[0725] Step B: Preparation of2-Bromo-1-(4-(2,6-difluorobenzyloxy)phenyl)-1-Ethanone:

[0726] To a stirred solution of copper (2) bromide (3.70 g, 16.6 mmol)in ethyl acetate (20 ml) was added a solution of4-(2,6-Difluorobenzyloxy)acetophenone (Step A, 2.74 g, 10.4 mmol) inchloroform (20 ml) at room temperature. The reaction mixture wasrefluxed for 16 hours and then water was added. The crude mixture wasextracted twice with EtOAc. The organic layers were combined and washedwith water, brine, dried over Na₂SO₄, filtered, concentrated andpurified by flash chromatography on silica gel column (hex:ethylacetate, 4:1) to provide the title compound as a white flaky solid.

[0727]¹H NMR (270 MHz, CDCl₃): 4.4 (s, 2H); 5.2 (s, 2H); 6.9-7.1 (m,4H), 7.3 (m, 1H); 8.0 (d, 2H).

[0728] Step C: Preparation of3-(2-(4-(2,6-Difluorobenzyloxy)phenyl)-2-oxoethyl)thio-1H-1,2,4-triazole:

[0729] To a solution of 1H-1,2,4-Triazole-3-thiol (0.250 g, 2.4 mmol)and triethylamine (2.50 g, 2.4 mmol) in dry dichloromethane (20 ml) wasadded 2-Bromo-1-(4-(2,6-difluorobenzyloxy)phenyl)-1-Ethanone (Step B,0.851 g, 2.4 mmol) in dry dichloromethane (5 ml) at room temperature.The reaction mixture was stirred for 50 minutes and then concentrated invacuo. The crude residue was taken in EtOAc and washed with 0.1M HCl,and brine. The organic layer was dried over Na₂SO₄, filtered,concentrated and purified by flash chromatography on silica gel column(chloroform:methanol, 9:1) to provide the title compound.

[0730]¹H NMR (270 MHz, CDCl₃): 4.5 (s, 2H); 5.1 (s, 2H); 6.8-7.0 (m,4H), 7.2 (m, 1H); 7.9 (d, 2H); 8.0 (s, 1H).

Example 30 Synthesis of5-((4-(2,6-Difluorobenzyloxy)phenyl)-methyl)-1H-tetrazole

[0731]

[0732] Step A: Preparation of(4-(2,6-Difluorobenzyloxy)phenyl)-acetonitrile:

[0733] To a solution of 4-Hydroxybenzyl cyanide (5 g, 37.5 mmol) andK₂CO₃ (6.74 g, 48.8 mmol) in dry DMF (20 ml) was added2,6-Difluorobenzyl bromide (7.77 g, 37.5 mmol). The reaction mixture wasstirred for 4 hours at room temperature and concentrated in vacuo. Thecrude residue was taken in EtOAc and washed with water and brine. Theaqueous layer was washed one more time with EtOAc. The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated to provide thetitle compound as a white solid.

[0734]¹H NMR (270 MHz, CDCl₃): 3.65 (s, 2H); 5.1 (s, 2H); 6.9-7.0 (m,4H); 7.2-7.4 (m, 3H);

[0735] Step B: Preparation of5-((4-(2,6-Difluorobenzyloxy)phenyl)-methyl)-1H-tetrazole:

[0736] A mixture of (4-(2,6-Difluorobenzyloxy)phenyl)-acetonitrile [StepA, 5 g, 19.3 mmol), NaN₃ (1.3 g, 20 mmol), and NH₄Cl (1.06 g, 20 mmol)in dry DMF (60 ml) was heated at 90° C. for 16 hours. The solvent wasremoved in vacuo and the oily residue was partitioned between EtOAc andwater (acidified to pH 1 with conc. HCl). The organic layer was washedwith water, dried over Na₂SO₄, filtered and concentrated to a brownsemisolid. The purification was done by flash chromatography on silicagel column (chloroform:methanol, 9:1) to provide the title compound as alight creamy solid.

[0737]¹H NMR (270 MHz, CDCl₃): 4.0 (s, 2H); 5.1 (s, 2H); 6.7-6.9 (m,4H); 7.0 (d, 2H); 7.2 (m, 1H).

Example 31 Synthesis of(2RS)2-(N-Boc)-3-[2-(4-(2,6-difluorobenzyloxy)phenyl)-2-oxoethyl]thiopropionicAcid

[0738]

[0739] Step A: Preparation of 4-(2,6-Difluorobenzyloxy)acetophenone:

[0740] To a solution of 4-Hydroxyacetophenone (3.28 g, 24 mmol) andK₂CO₃ (4.33 g, 31.3 mmol) in dry DMF (15 ml) was added2,6-Difluorobenzyl bromide (5 g, 24.1 mmol). The reaction mixture wasstirred at room temperature for 5 hours, quenched with water andconcentrated in vacuo. The crude residue was taken in EtOAc and washedwith water and brine. The aqueous layer was extracted twice with EtOAc.The combined organic layers were dried over Na₂SO₄, filtered,concentrated and purified by flash chromatography on silica gel column(hex:ethyl acetate, 2:1) to provide the title compound.

[0741]¹H NMR (270 MHz, CDCl₃): 2.5 (s, 3H); 5.2 (s, 2H); 6.9-7.0 (m,4H); 7.3-7.4 (m, 1H); 7.9 (d, 2H).

[0742] Step B: Preparation of2-Bromo-1-(4-(2,6-difluorobenzyloxy)phenyl)-1-Ethanone:

[0743] Using the method of Example 29, Step B, the title compound wasobtained.

[0744]¹H NMR (270 MHz, CDCl₃): 4.4 (s, 2H); 5.2 (s, 2H); 6.9-7.1 (m,4H), 7.3 (m, 1H); 8.0 (d, 2H).

[0745] Step C: Preparation of Ethyl(2RS)2-(N-Boc)-3-[2-(4-(2,6-difluorobenzyloxy)phenyl)-2-oxoethyl]thiopropionate:

[0746] To a stirred solution of2-Bromo-1-(4-(2,6-difluorobenzyloxy)phenyl)-1-Ethanone (Step B, 2.07 g,8.3 mmol) in dry dichloromethane (20 ml) and triethylamine (8.39 g, 83mmol) was added Boc-Cys-OEt (2.94 g, 8.6 mmol). The reaction mixture wasstirred at room temperature for an hour and concentrated in vacuo. Thecrude residue was taken in EtOAc, washed with 0.1M HCl, and brine. Theorganic layer was dried over Na₂SO₄, filtered, concentrated and purifiedby flash chromatography on silica gel column (chloroform:methanol,97.5:2.5) to provide the title compound.

[0747]¹H NMR (270 MHz, CDCl₃): 1.2 (t, 3H); 1.4 (s, 9H); 3.0 (m, 2H);3.8 (s, 2H); 4.2 (q, 2H); 4.5 (br, 1H); 5.2 (s, 2H); 5.4 (d, 1H);6.9-7.1 (m, 4H); 7.3 (m, 1H); 7.9 (d, 2H).

[0748] Step D: Preparation of(2RS)2-(N-Boc)-3-[2-(4-(2,6-difluorobenzyloxy)phenyl)-2-oxoethyl]thiopropionicAcid:

[0749] To a solution of Ethyl(2RS)2-(N-Boc)-3-[2-(4-(2,6-difluorobenzyloxy)phenyl)-2-oxoethyl]thiopropionate(Step C, 0.761 g, 1.5 mmol) in abs EtOH (10 ml) was added 1N NaOH (3ml). The reaction mixture was stirred at room temperature for 4 hours,acidified with 1M HCl and concentrated in vacuo. The crude residue wastaken in chloroform, and washed with water and brine. The organic layerwas dried over Na₂SO₄, filtered, concentrated and purified by flashchromatography on silica gel column (chloroform:methanol, 92.7:7.5) toprovide the title compound.

[0750]¹H NMR (270 MHz, CDCl₃): 1.4 (s, 9H); 3.0 (t, 2H); 4.0 (q, 2H);4.5 (br, 1H); 5.2 (s, 2H); 5.4 (d, 1H); 6.9-7.1 (m, 4H); 7.3 (m, 1H);7.9 (d, 2H).

Example 32 Synthesis of Ethyl2-Hydroxy-4-oxo-4-(4-(2,6-difluorobenzyloxy)phenyl) but-2-enoate

[0751]

[0752] Step A: Preparation of 4-(2,6-Difluorobenzyloxy)acetophenone:

[0753] Using the method of example 31, Step A, the title compound wasobtained.

[0754]¹H NMR (270 MHz, CDCl₃): 2.5 (s, 3H); 5.2 (s, 2H); 6.9-7.0 (m,4H); 7.3-7.4 (m, 1H); 7.9 (d, 2H).

[0755] Step B: Preparation of Ethyl2-Hydroxy-4-oxo-4-(4-(2,6-difluorobenzyloxy)phenyl) but-2-enoate:

[0756] A mixture of 4-(2,6-Difluorobenzyloxy)acetophenone (Step A, 5.64g, 21.5 mmol) and diethyl oxalate (3.14 g, 21.5 mmol) was added to anice-cooled solution of NaOEt (0.490 g, 22.4 mmol of metallic Na) in absEtOH (25 ml). After being allowed to stand overnight at roomtemperature, the mixture was diluted with water (50 ml), acidified with10% HCl, and extracted thrice with EtOAc. The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered, concentrated andpurified by flash chromatography on silica gel column (hex:ethylacetate, 4:1) to provide the title compound.

[0757]¹H NMR (270 MHz, CDCl₃): 1.4 (t, 3H); 4.4 (q, 2H); 5.2 (s, 2H);6.9-7.1 (m, 5H); 7.3-7.4 (m, 1H); 8.0 (d, 2H).

Example 33 Synthesis of(2RS)2-(N-Acetyl)-4-(4-(2,6-difluorobenzyloxy)phenyl)-4-oxobutyric Acid

[0758]

[0759] Step A: Preparation of 4-(2,6-Difluorobenzyloxy)acetophenone:

[0760] Using the method of example 31, Step A, the title compound wasobtained.

[0761]¹H NMR (270 MHz, CDCl₃): 2.5 (s, 3H); 5.2 (s, 2H); 6.9-7.0 (m,4H); 7.3-7.4 (m, 1H); 7.9 (d, 2H).

[0762] Step B: Preparation of2-Bromo-1-(4-(2,6-difluorobenzyloxy)phenyl)-1-Ethanone:

[0763] Using the method of Example 29, Step B, the title compound wasobtained.

[0764]¹H NMR (270 MHz, CDCl₃): 4.4 (s, 2H); 5.2 (s, 2H); 6.9-7.1 (m,4H), 7.3 (m, 1H); 8.0 (d, 2H).

[0765] Step C: Preparation of Diethyl(N-Acetyl)(2-(4-(2,6-difluorobenzyloxy)phenyl)-2-oxoethyl)propanedioate:

[0766] To a solution of Diethyl acetamidomalonate (0.949 g, 4.3 mmol)and NaOEt (0.301 g, 4.4 mmol) in abs EtOH (25 ml) was added2-Bromo-1-(4-(2,6-difluorobenzyloxy)phenyl)-1-Ethanone (Step B, 1.42 g,4.1 mmol). The reaction mixture was stirred at room temperature for 2hours and concentrated in vacuo. The crude residue was partitionedbetween EtOAc and 0.01 N NaOH. The organic layer was washed with waterand 0.001 M HCl, dried over Na₂SO₄, filtered and concentrated. Thepurification was done by flash chromatography on silica gel column(hex:ethyl acetate, 2:1) to provide the title compound.

[0767]¹H NMR (270 MHz, CDCl₃): 1.2 (t, 6H); 2.0 (s, 3H); 4.2-4.3 (m,6H); 5.2 (s, 2H); 6.9-7.1 (m, 4H), 7.3-7.4 (m, 1H); 7.9 (d, 2H).

[0768] Step D: Preparation of(2RS)2-(N-Acetyl)-4-(4-(2,6-difluorobenzyloxy)phenyl)-4-oxobutyric Acid:

[0769] To a solution of Diethyl(N-Acetyl)(2-(4-(2,6-difluorobenzyloxy)phenyl)-2-oxoethyl)propanedioate(Step C, 1.28 g, 2.6 mmol) in water (20 ml) was added NaOH (0.529 g,13.2 mmol). The reaction mixture was refluxed for 16 hours, then glacialacetic acid (18 ml) was added and refluxing continued for an additional3 hours. The mixture was concentrated in vacuo and purified by flashchromatography on silica gel column (chloroform:methanol, 9:1) toprovide the title compound.

[0770]¹H NMR (270 MHz, CDCl₃:CD₃OD): 2.0 (s, 3H); 3.5 (m, 2H); 4.8 (t,1H); 5.1 (s, 2H); 6.97.1 (m, 4H), 7.3-7.4 (m, 1H); 7.9 (d, 2H).

Example 34 Synthesis of 4-(3-((Cyclopropyl)-methoxy)phenyl)-4-oxobutyricAcid

[0771]

[0772] Step A: Preparation of 3-((Cyclopropyl)-methoxy)acetophenone:

[0773] Using the method of Example 31, Step A, using Cyclopropylmethylbromide and 3-Hydroxyacetophenone as the starting materials, the titlecompound was obtained.

[0774]¹H NMR (270 MHz, CDCl₃): 0.4 (m, 2H); 0.6 (m, 2H); 1.2 (m, 1H);2.5 (s, 3H); 3.8 (d, 2H); 7.1 (m, 1H); 7.4 (m, 1H); 7.5-7.6 (m, 2H).

[0775] Step B: Preparation of Tert-Butyl4-(3-((cyclopropyl)-methoxy)phenyl)-4-oxobutyrate:

[0776] Using the method of Example 8, Step B, the title compound wasobtained.

[0777]¹H NMR (270 MHz, CDCl₃): 0.4 (m, 2H); 0.6 (m, 2H); 1.2 (m, 1H);1.4 (s, 9H); 2.6 (t, 2H); 3.2 (t, 2H); 3.8 (d, 2H); 7.1 (m, 1H); 7.4 (m,1H); 7.5-7.6 (m, 2H).

[0778] Step C: Preparation of4-(3-((Cyclopropyl)-methoxy)phenyl)-4-oxobutyric Acid:

[0779] Using the method of Example 8, Step C, the title compound wasobtained.

[0780]¹H NMR (270 MHz, CDCl₃): 0.4 (m, 2H); 0.6 (m, 2H); 1.2 (m, 1H);2.8 (t, 2H); 3.2 (t, 2H); 3.8 (d, 2H); 7.1 (m, 1H); 7.4 (m, 1H); 7.5-7.6(m, 2H).

Example 35 Synthesis of 4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutyricAcid

[0781]

[0782] Step A: Preparation of 2,6-Dimethylbenzyl Alcohol:

[0783] To a solution of 2,6-dimethylbenzoic acid (10 g, 66.5 mmol) andpotassium carbonate (9.18 g, 66.5 mmol) in dimethylformamide (67 ml),was added methyl iodide (8.28 ml, 133.16 ml) in an ice bath, and themixture was stirred for 16 hours. To the reaction mixture was addedtoluene and water, and the organic layer was washed with 3% K₂CO₃, 1NHCl, and brine. The organic layer was dried over Na₂SO₄, filtered andconcentrated. The oily residue was redissolved in dry THF (135 ml),added to LiAlH₄ (3.79 g, 99.8 mmol), and stirred for 4 hours in an icebath. To the reaction mixture was added 1N HCl slowly followed by ethylacetate, and the organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated. The oily residue was used without furtherpurification.

[0784]¹H NMR (270 MHz, CDCl₃): 2.4 (s, 6H); 4.7 (s, 2H); 7.0-7.15 (m,3H).

[0785] Step B: Preparation of 3-(2,6-Dimethylbenzyloxy)acetophenone:

[0786] To a stirred solution of 3′-Hydroxyacetophenone (8.07 g, 59.24mmol) and Triphenylphosphine (16.93 g, 64.5 mmol) in dry THF (180 ml)was added dropwise 2,6-Dimethylbenzyl alcohol (8.05 g, 59.24 mmol) anddiethyl azodicarboxylate (11.24 g, 64.57 mmol) in dry THF (45 ml) anddry DMF (18 ml) at ambient temperature. After stirring for 1.5 hours atambient temperature, the reaction mixture was diluted with ether andwashed twice with water, 1N NaOH and brine, dried over Na₂SO₄, filteredand concentrated. The purification was done by flash chromatography onsilica gel column (hex:ethyl acetate, 2:1) to provide the titlecompound.

[0787]¹H NMR (270 MHz, CDCl₃): 2.4 (s, 6H); 2.6 (s, 3H); 5.1 (s, 2H);7.1 (dd, 2H); 7.2 (m, 2H); 7.4 (t, 1H); 7.6 (m, 2H).

[0788] Step C: Preparation of Ethyl4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-oxobutyrate:

[0789] Using the method of Example 17, Step B, the title compound wasobtained.

[0790]¹H NMR (270 MHz, CDCl₃): 1.2 (s, 3H); 2.4 (s, 6H); 2.8 (t, 2H);3.2 (t, 2H); 4.4 (q, 2H); 5.1 (s, 2H); 7.1 (d, 2H); 7.2 (m, 2H); 7.4 (t,1H); 7.6 (m, 2H).

[0791] Step-D: Preparation of4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutyric Acid:

[0792] To a solution of Ethyl4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-oxobutyrate (Step C, 12.31 g, 36.2mmol) in abs ethanol (160 ml) was added 1N NaOH (50 ml) at roomtemperature. The reaction mixture was stirred for 3 hours and thenacidified with 1M HCl. The occuring white precipitate was filtered,washed with water and dried under vacuum to provide the title compoundas a white solid.

[0793]¹H NMR (270 MHz, CDCl₃): 2.4 (s, 6H); 2.8 (t, 2H); 3.3 (t, 2H);5.1 (s, 2H); 7.1 (d, 2H); 7.2-7.3 (m, 2H); 7.4 (t, 1H); 7.6 (m, 2H).

Example 36 Synthesis of4-(3-(2-Fluoro-6-methylbenzyloxy)phenyl)-4-oxobutyric Acid

[0794]

[0795] Step A: Preparation of 2-Fluoro-6-methylbenzoic Acid:

[0796] Synthesized as described in Example 89(d) of International PatentPublication No. WO 97/34893, page 43.

[0797] Step B: Preparation of 2-Fluoro-6-methylbenzyl Alcohol:

[0798] Using the method of Example 35, Step A, the title compound wasobtained.

[0799]¹H NMR (270 MHz, CDCl₃): 2.4 (s, 3H); 4.7 (s, 2H); 6.85 (t, 1H);6.95 (d, 1H); 7.15 (m, 1H).

[0800] Step C: Preparation of3-(2-Fluoro-6-methylbenzyloxy)acetophenone:

[0801] Using the method of Example 35, Step B, the title compound wasobtained.

[0802]¹H NMR (270 MHz, CDCl₃): 2.4 (s, 3H); 2.6 (s, 3H); 5.1 (s, 2H);7.1 (m, 2H); 7.2 (m, 2H); 7.4 (t, 1H); 7.6 (m, 2H).

[0803] Step D: Preparation of Ethyl4-(3-(2-Fluoro-6-methylbenzyloxy)phenyl)-4-oxobutyrate:

[0804] Using the method of Example 17, Step B, the title compound wasobtained.

[0805]¹H NMR (270 MHz, CDCl₃): 1.2 (s, 3H); 2.4 (s, 3H); 2.8 (t, 2H);3.3 (t, 2H); 4.4 (q, 2H); 5.2 (s, 2H); 6.9-7.1 (m, 2H); 7.2 (m, 2H); 7.4(t, 1H); 7.6 (m, 2H).

[0806] Step E: Preparation of4-(3-(2-Fluoro-6-methylbenzyloxy)phenyl)-4-oxobutyric Acid:

[0807] To a solution of Ethyl4-(3-(2-Fluoro-6-methylbenzyloxy)phenyl)-4-oxobutyrate (Step D, 8.56 g,24.9 mmol) in abs ethanol (100 ml) was added 1N NaOH (40 ml) at roomtemperature. The reaction mixture was stirred for 3 hours, acidifiedwith 1M HCl and concentrated. The residue was taken in chloroform andwashed with 0.1 M HCl, brine, dried over Na₂SO₄, filtered andconcentrated. The purification was done by flash chromatography onsilica gel column (chloroform:methanol 95:5 spiked with acetic acid) toprovide the title compound as white solid.

[0808]¹H NMR (270 MHz, CDCl₃): 2.4 (s, 3H); 2.8 (t, 2H); 3.3 (t, 2H);5.1 (s, 2H); 6.9-7.1 (m, 2H); 7.2 (m, 2H); 7.4 (t, 1H); 7.6 (m, 2H).

Example 37 Synthesis of Ethyl4-(3-(2,6-dimethylbenzyloxyl)phenyl)-4-oxobutyrate

[0809]

[0810] Step A: Preparation of 2,6-Dimethylbenzyl Alcohol:

[0811] Using the method of Example 35, Step A, the title compound wasobtained.

[0812]¹H NMR (270 MHz, CDCl₃): 2.4 (s, 6H); 4.7 (s, 2H); 7.0-7.15 (m,3H).

[0813] Step B: Preparation of 3-(2,6-Dimethylbenzyloxy)acetophenone:

[0814] Using the method of Example 35, Step B, the title compound wasobtained.

[0815]¹H NMR (270 MHz, CDCl₃): 2.4 (s, 6H); 2.6 (s, 3H); 5.1 (s, 2H);7.1 (dd, 2H); 7.2 (m, 2H); 7.4 (t, 1H); 7.6 (m, 2H).

[0816] Step C: Preparation of Ethyl4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-oxobutyrate:

[0817] Using the method of Example 17, Step B, the title compound wasobtained.

[0818]¹H NMR (270 MHz, CDCl₃): 1.2 (s, 3H); 2.4 (s, 6H); 2.8 (t, 2H);3.2 (t, 2H); 4.4 (q, 2H); 5.1 (s, 2H); 7.1 (d, 2H); 7.2 (m, 2H); 7.4 (t,1H); 7.6 (m, 2H).

Example 38 Synthesis of 4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutyricAcid Sodium Salt

[0819]

[0820] Step A: Preparation of 2,6-Dimethylbenzyl Alcohol:

[0821] Using the method of Example 35, Step A, the title compound wasobtained.

[0822]¹H NMR (270 MHz, CDCl₃): 2.4 (s, 6H); 4.7 (s, 2H); 7.0-7.15 (m,3H).

[0823] Step B: Preparation of 3-(2,6-Dimethylbenzyloxy)acetophenone:

[0824] Using the method of Example 35, Step B, the title compound wasobtained.

[0825]¹H NMR (270 MHz, CDCl₃): 2.4 (s, 6H); 2.6 (s, 3H); 5.1 (s, 2H);7.1 (dd, 2H); 7.2 (m, 2H); 7.4 (t, 1H); 7.6 (m, 2H).

[0826] Step C: Preparation of Ethyl4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-oxobutyrate:

[0827] Using the method of Example 17, Step B, the title compound wasobtained.

[0828]¹H NMR (270 MHz, CDCl₃): 1.2 (s, 3H); 2.4 (s, 6H); 2.8 (t, 2H);3.2 (t, 2H); 4.4 (q, 2H); 5.1 (s, 2H); 7.1 (d, 2H); 7.2 (m, 2H); 7.4 (t,1H); 7.6 (m, 2H).

[0829] Step D: Preparation of4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutyric Acid:

[0830] Using the method of Example 36, Step E, the title compound wasobtained.

[0831]¹H NMR (270 MHz, CDCl₃): 2.4 (s, 6H); 2.8 (t, 2H); 3.3 (t, 2H);5.1 (s, 2H); 7.1 (d, 2H); 7.2-7.3 (m, 2H); 7.4 (t, 1H); 7.6 (m, 2H).

[0832] Step E: Preparation of4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutyric Acid Sodium Salt:

[0833] The 4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutyric acid (StepD, 5.5 g, 17.6 mmol) was dissolved in abs ethanol (20 ml) by warminggently followed by addition of NaOH (0.705 g) at 0° C. temperature. Thereaction mixture was stirred for one hour, concentrated in vaccuo andlyophilized to give as a white solid.

[0834]¹H NMR (270 MHz, D₂O): 2.0 (s, 6H); 2.5 (t, 2H); 3.0 (t, 2H); 4.8(s, 2H); 6.8 (d, 2H); 6.9 (m, 2H); 7.2 (t, 1H); 7.5 (d, 2H).

Example 39 Synthesis of 4-(4-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutyricAcid

[0835]

[0836] Step A: Preparation of 2,6-Dimethylbenzyl Alcohol:

[0837] Using the method of Example 35, Step A, the title compound wasobtained.

[0838]¹H NMR (270 MHz, CDCl₃): 2.4 (s, 6H); 4.7 (s, 2H); 7.0-7.15 (m,3H).

[0839] Step B: Preparation of 4-(2,6-Dimethylbenzyloxy)acetophenone:

[0840] Using the method of Example 35, Step B, the title compound wasobtained.

[0841]¹H NMR (270 MHz, CDCl₃): 2.4 (s, 6H); 2.6 (s, 3H); 5.1 (s, 2H);7.0-7.2 (m, 5H); 8.0 (d, 2H).

[0842] Step C: Preparation of Ethyl4-(4-(2,6-dimethylbenzyloxy)phenyl)-4-oxobutyrate:

[0843] Using the method of Example 17, Step B, the title compound wasobtained.

[0844]¹H NMR (270 MHz, CDCl₃): 1.2 (s, 3H); 2.4 (s, 6H); 2.8 (t, 2H);3.3 (t, 2H); 4.4 (q, 2H); 5.1 (s, 2H); 7.0-7.2 (m, 5H); 8.0 (d, 2H).

[0845] Step D: Preparation of4-(4-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutyric Acid:

[0846] Using the method of Example 36, Step E, the title compound wasobtained.

[0847]¹H NMR (270 MHz, CDCl₃): 2.4 (s, 6H); 2.8 (t, 2H); 3.3 (t, 2H);5.1 (s, 2H); 7.0-7.2 (m, 5H); 8.0 (d, 2H).

Example 40 Synthesis of 4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutyricAcid Potassium Salt

[0848]

[0849] Step A: Preparation of 2,6-Dimethylbenzyl Alcohol:

[0850] Using the method of Example 35, Step A, the title compound wasobtained.

[0851]¹H NMR (270 MHz, CDCl₃): 2.4 (s, 6H); 4.7 (s, 2H); 7.0-7.15 (m,3H).

[0852] Step B: Preparation of 3-(2,6-Dimethylbenzyloxy)acetophenone:

[0853] Using the method of Example 35, Step B, the title compound wasobtained.

[0854]¹H NMR (270 MHz, CDCl₃): 2.3 (s, 6H); 2.6 (s, 3H); 5.1 (s, 2H);7.1 (d, 2H); 7.2 (m, 2H); 7.45 (t, 1H); 7.6 (m, 2H).

[0855] Step C: Preparation of Ethyl4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-oxobutyrate:

[0856] Using the method of Example 17, Step B, the title compound wasobtained.

[0857]¹H NMR (270 MHz, CDCl₃): 1.2 (s, 3H); 2.4 (s, 6H); 2.8 (t, 2H);3.2 (t, 2H); 4.4 (q, 2H); 5.1 (s, 2H); 7.1 (d, 2H); 7.2 (m, 2H); 7.45(t, 1H); 7.6 (m, 2H).

[0858] Step D: Preparation of4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutyric Acid:

[0859] Using the method of Example 36, Step E, the title compound wasobtained.

[0860]¹H NMR (270 MHz, CDCl₃): 2.4 (s, 6H); 2.5 (t, 2H); 3.2 (t, 2H);5.1 (s, 2H); 7.1 (d, 2H); 7.2-7.3 (m, 2H); 7.45 (t, 1H); 7.6 (m, 2H).

[0861] Step E: Preparation of4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutyric Acid Potassium Salt:

[0862] The 4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutyric acid (StepD, 6.0 g, 19.4 mmol) was dissolved in abs ethanol (20 ml) by warminggently followed by addition of KOH (1.21 g) at 0° C. temperature. Thereaction mixture was stirred for one hour, concentrated in vaccuo andlyophilized to give the title compound as white solid.

[0863]¹H NMR (270 MHz, D₂O): 2.3 (s, 6H); 2.5 (t, 2H); 3.3 (t, 2H); 5.1(s, 2H); 7.1 (d, 2H); 7.2-7.3 (m, 2H); 7.45 (t, 1H); 7.6 (m, 2H).

Example 41 Synthesis of4-(3-(2,6-Dimethoxybenzyloxy)phenyl)-4-oxobutyric Acid

[0864]

[0865] Step A: Preparation of 2,6-Dimethoxy]benzyl Alcohol:

[0866] Using the method of Example 35, Step A, the title compound wasobtained.

[0867]¹H NMR (270 MHz, CDCl₃): 3.9 (s, 6H); 4.8 (s, 2H); 6.5 (d, 2H);7.25 (m, 1H).

[0868] Step B: Preparation of 3-(2,6-Dimethoxybenzyloxy)acetophenone:

[0869] Using the method of Example 35, Step B, the title compound wasobtained.

[0870]¹H NMR (270 MHz, CDCl₃): 2.6 (s, 3H); 3.9 (s, 6H); 5.2 (s, 2H);6.6 (d, 2H); 7.3 (m, 3H); 7.5 (d, 1H); 7.7 (d, 1H).

[0871] Step C: Preparation of Ethyl4-(3-(2,6-dimethoxybenzyloxy)phenyl)-4-oxobutyrate:

[0872] Using the method of Example 17, Step B, the title compound wasobtained.

[0873]¹H NMR (270 MHz, CDCl₃): 1.2 (t, 3H); 2.8 (t, 2H); 3.3 (t, 2H);3.8 (s, 6H); 4.1 (q, 2H); 5.2 (s, 2H); 6.5 (d, 2H); 7.3-7.4 (m, 3H); 7.6(d, 1H); 7.7 (d, 1H).

[0874] Step D: Preparation of4-(3-(2,6-dimethoxybenzyloxy)phenyl)-4-oxobutyric Acid:

[0875] Using the method of Example 36, Step E, the title compound wasobtained.

[0876]¹H NMR (270 MHz, CDCl₃): 2.8 (t, 2H); 3.3 (t, 2H); 3.8 (s, 6H);5.2 (s, 2H); 6.5 (d, 2H); 7.3-7.4 (m, 3H); 7.6 (d, 1H); 7.7 (d, 1H).

Example 42 Synthesis of4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxo-2,2-dimethylbutyric Acid:

[0877]

[0878] Step A: Preparation of 2,6-Dimethylbenzyl Alcohol:

[0879] Using the method of Example 35, Step A, the title compound wasobtained.

[0880]¹H NMR (270 MHz, CDCl₃): 2.4 (s, 6H); 4.7 (s, 2H); 7.0-7.15 (m,3H).

[0881] Step B: Preparation of 3-(2,6-Dimethylbenzyloxy)acetophenone:

[0882] Using the method of Example 35, Step B, the title compound wasobtained.

[0883]¹H NMR (270 MHz, CDCl₃): 2.4 (s, 6H); 2.6 (s, 3H); 5.1 (s, 2H);7.1 (dd, 2H); 7.2 (m, 2H); 7.4 (t, 1H); 7.6 (m, 2H).

[0884] Step C: Preparation of Ethyl4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-oxo-2,2-dimethylbutyrate:

[0885] To a stirred solution of 3-(2,6-Dimethylbenzyloxy)acetophenone(Step B, 4.11 g, 16.1 mmol) in dry THF (60 ml) and DMPU (12 ml) wasadded a solution of lithium bis(trimethylsilyl)amide (1.0M, 17.74 ml) at−60° C. under argon. After stirring for 10 minutes at −60° C., Ethyl2-bromoisobutyrate (4.73 g, 24.2 mmol) was added rapidly. The reactionmixture was stirred for an additional 10 minutes and then warmed to roomtemperature for 4 hours. The crude mixture was taken in EtOAc and washedwith water. The aqueous layer was extracted one more time with EtOAc.The combined organic layers were washed with brine, dried over Na₂SO₄,filtered, concentrated and purified by flash chromatography on silicagel column (hex:ethyl acetate, 4:1) to provide the title compound aswhite solid.

[0886]¹H NMR (270 MHz, CDCl₃): 1.2 (t, 3H); 1.3 (s, 6H); 2.3 (s, 6H);3.3 (s, 2H); 4.1 (q, 2H); 5.1 (s, 2H); 7.1 (d, 2H); 7.2 (m, 2H); 7.4 (t,1H); 7.6 (m, 2H).

[0887] Step D: Preparation of4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxo-2,2-dimethylbutyric Acid:

[0888] Using the method of Example 36, Step E, the title compound wasobtained.

[0889]¹H NMR (270 MHz, CDCl₃): 1.3 (s, 6H); 2.3 (s, 6H); 3.3 (s, 2H);5.1 (s, 2H); 7.1 (d, 2H); 7.2 (m, 2H); 7.4 (t, 1H); 7.6 (m, 2H).

Example 43 Synthesis of4-(3-(4-(Trifluoromethyl)benzyloxy)phenyl)-4-oxobutyric Acid:

[0890]

[0891] Step A: Preparation of3-(4-(Trifluoromethyl)benzyloxy)acetophenone:

[0892] Using the method of Example 31, Step A, using4-(Trifluoromethyl)benzyl bromide and 3-Hydroxyacetophenone as thestarting materials, the title compound was obtained.

[0893]¹H NMR (270 MHz, CDCl₃): 2.5 (s, 3H); 5.1 (s, 2H); 7.1 (d, 2H);7.4-7.6 (m, 6H).

[0894] Step B: Preparation of Ethyl4-(3-(4-(trifluoromethyl)benzyloxy)phenyl)-4-oxobutyrate:

[0895] Using the method of Example 17, Step B, the title compound wasobtained.

[0896]¹H NMR (270 MHz, CDCl₃): 1.3 (t, 3H); 2.7 (t, 2H); 3.3 (t, 2H);4.1 (q, 2H); 5.1 (s, 2H); 7.1 (d, 2H); 7.4-7.6 (m, 6H).

[0897] Step C: Preparation of4-(3-(4-(Trifluoromethyl)benzyloxy)phenyl)-4-oxobutyric Acid:

[0898] Using the method of Example 36, Step E, the title compound wasobtained.

[0899]¹H NMR (270 MHz, CDCl₃): 2.7 (t, 2H); 3.3 (t, 2H); 5.1 (s, 2H);7.1 (d, 2H); 7.4-7.6 (m, 6H).

Example 44 Synthesis of 4-(3-((Cyclobutyl)-methoxy)phenyl)-4-oxobutyricAcid

[0900]

[0901] Step A: Preparation of 3-((Cyclobutyl)-methoxy)acetophenone:

[0902] Using the method of Example 31, Step A, using Cyclobutylmethylbromide and 3-Hydroxyacetophenone as the starting materials, the titlecompound was obtained.

[0903]¹H NMR (270 MHz, CDCl₃): 1.9 (m, 4H); 2.1 (m, 2H); 2.5 (s, 3H);2.7 (m, 1H); 4.0 (d, 2H); 7.1 (dd, 1H); 7.4 (t, 1H); 7.5-7.6 (m, 2H).

[0904] Step B: Preparation of Ethyl4-(3-((cyclobutyl)-methoxy)phenyl)-4-oxobutyrate:

[0905] Using the method of Example 35, Step C, the title compound wasobtained.

[0906]¹H NMR (270 MHz, CDCl₃): 1.2 (t, 3H); 1.9 (m, 4H); 2.1 (m, 2H);2.7 (m, 1H); 2.8 (t, 2H); 3.3 (t, 2H); 4.0 (d, 2H); 4.1 (q, 2H); 7.1(dd, 1H); 7.4 (t, 1H); 7.5-7.6 (m, 2H).

[0907] Step C: Preparation of4-(3-((Cyclobutyl)-methoxy)phenyl)-4-oxobutyric Acid:

[0908] Using the method of Example 36, Step E, the title compound wasobtained.

[0909]¹H NMR (270 MHz, CDCl₃): 1.9 (m, 4H); 2.1 (m, 2H); 2.7 (m, 1H);2.8 (t, 2H); 3.3 (t, 2H); 4.0 (d, 2H); 7.1 (dd, 1H); 7.4 (t, 1H);7.5-7.6 (m, 2H).

Example 45 Synthesis of 4-(3-(2,6-Dimethylbenzyloxy)phenyl)butyric Acid

[0910]

[0911] Step A: Preparation of 2,6-Dimethylbenzyl Alcohol:

[0912] Using the method of Example 35, Step A, the title compound wasobtained.

[0913]¹H NMR (270 MHz, CDCl₃): 2.4 (s, 6H); 4.7 (s, 2H); 7.0-7.15 (m,3H).

[0914] Step B: Preparation of 3-(2,6-Dimethylbenzyloxy)acetophenone:

[0915] Using the method of Example 35, Step B, the title compound wasobtained.

[0916]¹H NMR (270 MHz, CDCl₃): 2.4 (s, 6H); 2.6 (s, 3H); 5.1 (s, 2H);7.1 (dd, 2H); 7.2 (m, 2H); 7.4 (t, 1H); 7.6 (m, 2H).

[0917] Step C: Preparation of Ethyl4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-oxobutyrate:

[0918] Using the method of Example 17, Step B, the title compound wasobtained.

[0919]¹H NMR (270 MHz, CDCl₃): 1.2 (s, 3H); 2.4 (s, 6H); 2.8 (t, 2H);3.2 (t, 2H); 4.4 (q, 2H); 5.1 (s, 2H); 7.1 (d, 2H); 7.2 (m, 2H); 7.4 (t,1H); 7.6 (m, 2H).

[0920] Step D: Preparation of4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutyric Acid:

[0921] Using the method of Example 36, Step E, the title compound wasobtained.

[0922]¹H NMR (270 MHz, CDCl₃): 2.4 (s, 6H); 2.8 (t, 2H); 3.3 (t, 2H);5.1 (s, 2H); 7.1 (d, 2H); 7.2-7.3 (m, 2H); 7.4 (t, 1H); 7.6 (m, 2H).

[0923] Step E: Preparation of 4-(3-(2,6-Dimethylbenzyloxy)phenyl)butyricAcid:

[0924] A solution of 4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutyricacid (Step D, 3 g, 9.6 mmol), hydrazine (1.41 ml, 28.8 mmol) andpotassium hydroxide (1.61 g, 28.8 mmol) in ethylene glycol (12 ml) wasrefluxed for 4 h, water (18 ml) and 6 N HCl (10 ml) were added to thereaction mixture. The crude reaction mixture was concentrated, and theresidue was dissolved in EtOAc, washed with water and brine, dried overNa₂SO₄, filtered, and concentrated. The purification was done by flashchromatography on silica gel column (chloroform:methanol 95:5 spikedwith acetic acid) to provide the title compound as a white solid.

[0925]¹H NMR (270 MHz, CDCl₃): 2.4 (m, 8H); 2.8 (t, 2H); 3.3 (t, 2H);5.1 (s, 2H); 7.1 (d, 2H); 7.2-7.3 (m, 2H); 7.4 (t, 1H); 7.6 (m, 2H).

Example 46 Synthesis of4-[[4-(2,6-Dimethylbenzyloxy)-3-methoxy]phenyl]-4-oxobutyric Acid

[0926]

[0927] Step A: Preparation of 2,6-Dimethylbenzyl Alcohol:

[0928] Using the method of Example 35, Step A, the title compound wasobtained.

[0929]¹H NMR (270 MHz, CDCl₃): 2.4 (s, 6H); 4.7 (s, 2H); 7.0-7.15 (m,3H).

[0930] Step B: Preparation of4-(2,6-Dimethylbenzyloxy)-3-methoxyacetophenone:

[0931] Using the method of Example 35, Step B, the title compound wasobtained.

[0932]¹H NMR (270 MHz, CDCl₃): 2.4 (s, 6H); 2.6 (s, 3H); 3.9 (s, 3H);5.1 (s, 2H); 7.1 (d, 2H); 7.2 (m, 2H); 7.6 (m, 2H).

[0933] Step C: Preparation of Ethyl4-[[4-(2,6-dimethylbenzyloxy)-3-methoxy]phenyl]-4-oxobutyrate:

[0934] Using the method of Example 17, Step. B, the title compound wasobtained.

[0935]¹H NMR (270 MHz, CDCl₃): 1.2 (s, 3H); 2.4 (s, 6H); 2.8 (t, 2H);3.3 (t, 2H); 3.9 (s, 3H); 4.4 (q, 2H); 5.1 (s, 2H); 7.0-7.2 (m, 4H); 7.6(m, 2H).

[0936] Step D: Preparation of4-[[4-(2,6-Dimethylbenzyloxy)-3-methoxy]phenyl]-4-oxobutyric Acid:

[0937] Using the method of Example 36, Step E, the title compound wasobtained.

[0938]¹H NMR (270 MHz, CDCl₃): 2.4 (s, 6H); 2.8 (t, 2H); 3.3 (t, 2H);3.9 (s, 3H); 5.1 (s, 2H); 7.0-7.2 (m, 4H); 7.6 (m, 2H).

Example 47 Synthesis of4-{3-[((4-Trifluoromethylbenzylamino)-carbonyl)-4-methoxy]phenyl}-4-oxobutyricAcid

[0939]

[0940] Step A: Preparation of Methyl 2-methoxy-5-acetylbenzoate:

[0941] To a stirred solution of Methyl 2-hydroxy-5-acetylbenzoate (12 g,61.7 mmol) in DMF (200 ml) was added cesium carbonate (24.15 g, 74.1mmol) and MeI (9.64 g, 68 mmol). The reaction mixture was stirred for 16hours at 0° C. and then diluted with ethyl acetate, washed with aqNa₂S₂O₅, brine, dried over Na₂SO₄, filtered and concentrated. Thepurification was done by flash chromatography on silica gel column(ethyl acetate:hexane 1:2) to provide the title compound as an off whitesolid.

[0942]¹H NMR (270 MHz, DMSO): 2.6 (s, 3H); 3.8 (s, 3H); 3.9 (s, 3H); 7.3(d, 1H); 8.1 (dd, 1H); 8.2 (s, 1H).

[0943] Step B: Preparation of 2-Methoxy-5-acetylbenzoic Acid:

[0944] Methyl 2-methoxy-5-acetylbenzoate (Step A, 3 g, 14.4 mmol) wasdissolved in acetic acid (80 ml) and then treated with c HCl (28 ml).The reaction mixture was refluxed for 4 hours, concentrated underreduced pressure and lyophilized to provide the title compound as creamcolor solid, which was used without further purification.

[0945]¹H NMR (270 MHz, DMSO): 2.6 (s, 3H); 3.9 (s, 3H); 7.3 (d, 1H); 8.1(dd, 1H); 8.2 (s, 1H).

[0946] Step C: Preparation of5-Acetyl-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl]benzamide:

[0947] To a stirred solution of 2-Methoxy-5-acetylbenzoic acid (Step B,2.5 g, 12.8 mmol), HOBt.H₂O (2.08 g, 15.4 mmol), and EDC (3.70 g, 19.3mmol) in CH₂Cl₂ (20 ml) and DMF (5 ml) was added4-(Trifluoromethyl)benzylamine (2.48 g, 14.1 mmol), and the mixture wasstirred for 16 hours at room temperature. The reaction mixture wasconcentrated under reduced pressure and then redissolved in ethylacetate. The organic layer was washed with 3% K₂CO₃, 1 N HCl, and brine,dried over Na₂SO₄, filtered and concentrated. The purification was doneby flash chromatography on silica gel column (chloroform:methanol 95:5)to provide the title compound as white solid.

[0948]¹H NMR (270 MHz, CDCl₃): 2.6 (s, 3H); 4.0 (s, 3H); 4.8 (d, 2H);7.0 (d, 1H); 7.5 (d, 2H); 7.6 (d, 2H); 8.1 (dd, 1H); 8.8 (s, 1H).

[0949] Step D: Preparation of Ethyl4-{3-[((4-Trifluoromethylbenzylamino)-carbonyl)-4-methoxy]phenyl}-4-oxobutyrate:

[0950] Using the method of Example 17, Step B, the title compound wasobtained.

[0951]¹H NMR (270 MHz, CDCl₃): 1.2 (s, 3H); 2.6 (t, 2H); 3.3 (t, 2H);4.0 (s, 3H); 4.4 (q, 2H); 4.8 (s, 2H); 7.0 (d, 1H); 7.4 (d, 2H); 7.6 (d,2H); 8.1 (dd, 1H); 8.8 (s, 1H).

[0952] Step E: Preparation of4-{3-[((4-Trifluoromethylbenzylamino)-carbonyl)-4-methoxy]phenyl}-4-oxobutyricAcid:

[0953] Using the method of Example 36, Step E, the title compound wasobtained.

[0954]¹H NMR (270 MHz, CDCl₃: CD₃OD): 2.6 (t, 2H); 3.3 (t, 2H); 4.0 (s,3H); 4.7 (s, 2H); 7.0 (d, 1H); 7.4 (d, 2H); 7.6 (d, 2H); 8.1 (dd, 1H);8.8 (s, 1H).

Example 48 Synthesis of4-{3-[((2,6-Dimethylbenzylamino)-carbonyl)-4-methoxy]phenyl}-4-oxobutyricAcid

[0955]

[0956] Step A: Preparation of 2,6-Dimethylbenzyl Alcohol:

[0957] Using the method of Example 35, Step A, the title compound wasobtained.

[0958]¹H NMR (270 MHz, CDCl₃): 2.4 (s, 6H); 4.7 (s, 2H); 7.0-7.15 (m,3H).

[0959] Step B: Preparation of N-(2,6-Dimethylbenzyl)phthalimide:

[0960] To a stirred solution of 2,6-Dimethylbenzyl Alcohol (Step A, 6.59g, 48.4 mmol) in DMSO (20 ml) was added chlorotrimethylsilane (15.75 ml,145 mmol) at room temperature, and the mixture was stirred for one hr.To this reaction mixture were added ethyl acetate and water, the organiclayer was washed with brine, dried over Na₂SO₄, filtered andconcentrated to give an oil. The oily residue was redissolved in DMF(100 ml) and potassium phthalimide (10.76 g, 58.1 mmol) was added. Thereaction mixture was stirred for 16 hours at room temperature, ethylacetate was added, and the organic layer was washed with 3% Na₂CO₃, 1 NHCl, dried over Na₂SO₄, filtered and concentrated to give white solid.The purification was done by flash chromatography on silica gel column(chloroform:methanol 95:5) to provide the title compound as white solid.

[0961]¹H NMR (270 MHz, DMSO): 2.3 (s, 6H); 4.8 (s, 2H); 7.0 (m, 3H); 7.8(s, 4H).

[0962] Step C: Preparation of 2,6-Dimethylbenzyl Amine:

[0963] To a stirred solution of N-(2,6-Dimethylbenzyl)phthalimide (StepB, 7.77 g, 29.3 mmol) in ethanol (80 ml) was added hydrazine monohydrate(2.16 ml, 44.52 mmol) and the reaction mixture was refluxed for 3.5hours. To this reaction mixture was added c HCl to bring pH to 1 andrefluxing continued for another 3.5 hours, water was added and reactionmixture was filtered, the filtrate was concentrated and pH was adjustedto 10 with 2 N NaOH. The residue was taken in methylene chloride andwashed with brine, dried over Na₂SO₄, filtered and concentrated to givean oil which was used without further purification.

[0964]¹H NMR (270 MHz, DMSO): 2.3 (s, 6H); 3.8 (s, 2H); 7.0 (m, 3H).

[0965] Step D: Preparation of5-Acetyl-2-methoxy-N-[[2,6-dimethyl)phenyl]methyl]benzamide:

[0966] To a stirred solution of 2-Methoxy-5-acetylbenzoic acid (Example47, Step B, 2.5 g, 12.8 mmol), HOBt (2.08 g, 15.4 mmol), and EDC (3.70g, 19.3 mmol) in CH₂Cl₂ (20 ml) and DMF (5 ml) was added2,6-Dimethylbenzyl amine (Step C, 1.72 g, 12.8 mmol), and the mixturewas stirred for 16 hours at room temperature. The reaction mixture wasconcentrated under reduced pressure and then redissolved in ethylacetate. The organic layer was washed with 3% K₂CO₃, 1 N HCl, and brine,dried over Na₂SO₄, filtered and concentrated. The purification was doneby flash chromatography on silica gel column (chloroform:methanol 95:5)to provide the title compound as white solid.

[0967]¹H NMR (270 MHz, CDCl₃): 2.5 (s, 6H); 2.6 (s, 3H); 3.9 (s, 3H);4.7 (s, 2H); 7.0 (d, 1H); 7.2 (m, 3H); 7.6 (br, 1H); 8.1 (dd, 1H); 8.8(s, 1H).

[0968] Step E: Preparation of Ethyl4-{3-[((2,6-Dimethylbenzylamino)-carbonyl)-4-methoxy]phenyl}-4-oxobutyrate:

[0969] Using the method of Example 17, Step B, the title compound wasobtained.

[0970]¹H NMR (270 MHz, CDCl₃): 1.2 (t, 3H); 2.4 (s, 6H); 2.7 (t, 2H);3.3 (t, 2H); 3.9 (s, 3H); 4.4 (q, 2H); 4.7 (s, 2H); 7.0 (m, 3H); 7.2 (m,1H); 8.1 (dd, 1H); 8.7 (s, 1H).

[0971] Step F: Preparation of4-{3-[((2,6-Dimethylbenzylamino)-carbonyl)-4-methoxy]phenyl}-4-oxobutyricAcid:

[0972] Using the method of Example 36, Step E, the title compound wasobtained.

[0973]¹H NMR (270 MHz, CDCl₃: CD₃OD): 2.4 (s, 6H); 2.7 (t, 2H); 3.3 (t,2H); 3.9 (s, 3H); 4.7 (s, 2H); 7.0 (m, 3H); 7.2 (m, 1H); 8.1 (dd, 1H);8.7 (s, 1H).

Example 49 Synthesis of4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutanecarbohydroxamic Acid:

[0974]

[0975] Step A: Preparation of 2,6-Dimethylbenzyl Alcohol:

[0976] Using the method of Example 35, Step A, the title compound wasobtained.

[0977]¹H NMR (270 MHz, CDCl₃): 2.4 (s, 6H); 4.7 (s, 2H); 7.0-7.15 (m,3H).

[0978] Step B: Preparation of 3-(2,6-Dimethylbenzyloxy)acetophenone:

[0979] Using the method of Example 35, Step B, the title compound wasobtained.

[0980]¹H NMR (270 MHz, CDCl₃): 2.4 (s, 6H); 2.6 (s, 3H); 5.1 (s, 2H);7.1 (dd, 2H); 7.2 (m, 2H); 7.4 (t, 1H); 7.6 (m, 2H).

[0981] Step C: Preparation of Ethyl4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-oxobutyrate:

[0982] Using the method of Example 17, Step B, the title compound wasobtained.

[0983]¹H NMR (270 MHz, CDCl₃): 1.2 (s, 3H); 2.4 (s, 6H); 2.8 (t, 2H);3.2 (t, 2H); 4.4 (q, 2H); 5.1 (s, 2H); 7.1 (d, 2H); 7.2 (m, 2H); 7.4 (t,1H); 7.6 (m, 2H).

[0984] Step D: Preparation of4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutanecarbohydroxamic Acid:

[0985] To a hydroxylamine hydrochloride solution in dry ethanol, add asolution of potassium hydroxide in dry ethanol at 35° C. Cool the mixand add Ethyl 4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-oxobutyrate (StepC), and powdered potassium hydroxide. After few hours, reaction mixturecan be diluted with water and neutralize with hydrochloric acid, filterand recrystallize to give title compound.

Example 50 Synthesis of4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutyramide

[0986]

[0987] Step A: Preparation of 2,6-Dimethylbenzyl Alcohol:

[0988] Using the method of Example 35, Step A, the title compound wasobtained.

[0989]¹H NMR (270 MHz, CDCl₃): 2.4 (s, 6H); 4.7 (s, 2H); 7.0-7.15 (m,3H).

[0990] Step B: Preparation of 3-(2,6-Dimethylbenzyloxy)acetophenone:

[0991] Using the method of Example 35, Step B, the title compound wasobtained.

[0992]¹H NMR (270 MHz, CDCl₃): 2.4 (s, 6H); 2.6 (s, 3H); 5.1 (s, 2H);7.1 (dd, 2H); 7.2 (m, 2H); 7.4 (t, 1H); 7.6 (m, 2H).

[0993] Step C: Preparation of Ethyl4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-oxobutyrate:

[0994] Using the method of Example 17, Step B, the title compound wasobtained.

[0995]¹H NMR (270 MHz, CDCl₃): 1.2 (s, 3H); 2.4 (s, 6H); 2.8 (t, 2H);3.2 (t, 2H); 4.4 (q, 2H); 5.1 (s, 2H); 7.1 (d, 2H); 7.2 (m, 2H); 7.4 (t,1H); 7.6 (m, 2H).

[0996] Step D: Preparation of4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutyric Acid:

[0997] Using the method of Example 35, Step D, the title compound wasobtained.

[0998]¹H NMR (270 MHz, CDCl₃): 2.4 (s, 6H); 2.8 (t, 2H); 3.3 (t, 2H);5.1 (s, 2H); 7.1 (d, 2H); 7.2-7.3 (m, 2H); 7.4 (t, 1H); 7.6 (m, 2H).

[0999] Step E: Preparation of4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutyramide:

[1000] To a solution of 4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutyricacid (Step D) in DMF, add triethylamine and BOP, after couple of hoursof stirring, reaction mixture can be added to liquid ammonia at −40° C.and the resulting mixture can be warmed for 16 hours to give titlecompound.

Example 51 Synthesis of4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxo-2-butenoic Acid

[1001]

[1002] Step A: Preparation of 2,6-Dimethylbenzyl Alcohol:

[1003] Using the method of Example 35, Step A, the title compound wasobtained.

[1004]¹H NMR (270 MHz, CDCl₃): 2.4 (s, 6H); 4.7 (s, 2H); 7.0-7.15 (m,3H).

[1005] Step B: Preparation of 3-(2,6-Dimethylbenzyloxy)acetophenone:

[1006] Using the method of Example 35, Step B, the title compound wasobtained.

[1007]¹H NMR (270 MHz, CDCl₃): 2.4 (s, 6H); 2.6 (s, 3H); 5.1 (s, 2H);7.1 (dd, 2H); 7.2 (m, 2H); 7.4 (t, 1H); 7.6 (m, 2H).

[1008] Step C: Preparation of Ethyl4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-oxobutyrate:

[1009] Using the method of Example 17, Step B, the title compound wasobtained.

[1010]¹H NMR (270 MHz, CDCl₃): 1.2 (s, 3H); 2.4 (s, 6H); 2.8 (t, 2H);3.2 (t, 2H); 4.4 (q, 2H); 5.1 (s, 2H); 7.1 (d, 2H); 7.2 (m, 2H); 7.4 (t,1H); 7.6 (m, 2H).

[1011] Step D: Preparation of Ethyl4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-oxo-3-bromo-butyrate:

[1012] To a ice cooled solution of Ethyl4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-oxobutyrate (Step C, 3 g, 9 mmol)in dry ether (70 ml) was added dropwise bromine (0.7971 g, 9.9 mmol)diluted in ether (30 ml). After 4 hours of stirring, reaction mixturewas concentrated and purified by flash chromatography on silica gelcolumn (EtOAc:Hex, 1:4) to provide the title compound.

[1013]¹H NMR (270 MHz, CDCl₃): 1.2 (s, 3H); 2.4 (s, 6H); 3.1 (m, 1H);3.5 (m, 1H); 4.2 (q, 2H); 5.1 (s, 2H); 5.5 (m, 1H); 7.1 (d, 2H); 7.2 (m,2H); 7.4 (t, 1H); 7.6 (m, 2H).

[1014] Step E: Preparation of Ethyl4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-oxo-2-butenoate:

[1015] Triethylamine (5.95 g, 58.9 mmol) was added to a solution ofEthyl 4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-oxo-3-bromo-butyrate (StepD, 2.47 g, 5.8 mmol) in carbon tetrachloride (50 ml). After stirring for4 hours at room temperature, the reaction mixture was filtered through apad of silica gel few times, and concentrated to give the titlecompound.

[1016]¹H NMR (270 MHz, CDCl₃): 1.2 (s, 3H); 2.4 (s, 6H); 4.2 (q, 2H);5.1 (s, 2H); 6.9 (dd, 1H); 7.1 (d, 2H); 7.2 (m, 2H); 7.4 (t, 1H); 7.6(m, 2H); 7.9 (dd, 1H).

[1017] Step F: Preparation of4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxo-2-butenoic Acid:

[1018] To a solution of Ethyl4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-oxo-2-butenoate (Step E) in absethanol at low temp, add aqueous sodium hydroxide, after an hour,concentrate and purify by flash chromatography on silica gel column(chloroform:methanol 95:5 spiked with acetic acid).

Example 52 Synthesis of 4-(3-(2,6-Dimethylbenzyloxy)phenyl)-3-butenoicAcid

[1019]

[1020] Step A: Preparation of 2,6-Dimethylbenzyl Alcohol:

[1021] Using the method of Example 35, Step A, the title compound wasobtained.

[1022]¹H NMR (270 MHz, CDCl₃): 2.4 (s, 6H); 4.7 (s, 2H); 7.0-7.15 (m,3H).

[1023] Step B: Preparation of 3-(2,6-Dimethylbenzyloxy)acetophenone:

[1024] Using the method of Example 35, Step B, the title compound wasobtained.

[1025]¹H NMR (270 MHz, CDCl₃): 2.4 (s, 6H); 2.6 (s, 3H); 5.1 (s, 2H);7.1 (dd, 2H); 7.2 (m, 2H); 7.4 (t, 1H); 7.6 (m, 2H).

[1026] Step C: Preparation of Ethyl4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-oxobutyrate:

[1027] Using the method of Example 17, Step B, the title compound wasobtained.

[1028]¹H NMR (270 MHz, CDCl₃): 1.2 (s, 3H); 2.4 (s, 6H); 2.8 (t, 2H);3.2 (t, 2H); 4.4 (q, 2H); 5.1 (s, 2H); 7.1 (d, 2H); 7.2 (m, 2H); 7.4 (t,1H); 7.6 (m, 2H).

[1029] Step D: Preparation of Ethyl4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-hydroxy-butyrate:

[1030] To a solution of Ethyl4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-oxobutyrate (Step C) intetrahydrofuran, add sodium borohydride dissolved in water, After 3-4hours of stirring at room temperature, quench with an acid. The organiclayer can be taken in dichloromethane, wash with water, aqueous sodiumbicarbonate, and brine, dry over Na₂SO₄, filter and concentrate. Ifneeded, the compound can be purified by flash chromatography on silicagel column (EtOAc:Hex).

[1031] Step E: Preparation of Ethyl4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-bromo-butyrate:

[1032] To a solution of Ethyl4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-hydroxy-butyrate (Step D) indioxane, add phosphorous tribromide in dioxane dropwise. After stirringat room temperature for 16 hours, quench with water and chloroform.After few minutes, the reaction mixture can be neutralized by mildaqueous base, dry organic layer over Na₂SO₄, filter, concentrate andpurify by flash chromatography on silica gel column (EtOAc:hex).

[1033] Step F: Preparation of Ethyl4-(3-(2,6-dimethylbenzyloxy)phenyl)-3-butenoate:

[1034] Add Triethylamine to a solution of Ethyl4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-bromo-butyrate (Step E) in carbontetrachloride. After stirring approximately for 4 hours, the mixture canbe filtered through a pad of silica gel few times, and concentrate togive the title compound.

[1035] Step G: Preparation of4-(3-(2,6-Dimethylbenzyloxy)phenyl)-3-butenoic Acid:

[1036] To a solution of Ethyl4-(3-(2,6-dimethylbenzyloxy)phenyl)-3-butenoate (Step F) in abs ethanolat low temp, add aqueous sodium hydroxide, after an hour, concentrateand purify by flash chromatography on silica gel column(chloroform:methanol 95:5 spiked with acetic acid).

BIOLOGICAL ACTIVITY EXAMPLES Example A Compound AH Improves MetabolicAbnormalities in Insulin-Dependent Diabetes

[1037] Streptozotocin (STZ) is a toxin that selectively destroysinsulin-producing pancreatic beta cells, and is widely used to induceinsulin-dependent diabetes in experimental animals.

[1038] Female Balb/C mice (8 weeks old; 18-20 grams body weight) weretreated with streptozotocin (STZ) (50 mg/kg i.p. on each of fiveconsecutive days). Fourteen days after the last dose of STZ, bloodglucose was measured to verify that the animals were diabetic, and themice were divided into two groups of 5 animals each, one group receivingCompound AH (250 mg/kg) daily by oral gavage, and the other receivingvehicle (0.75% hydroxypropylmethylcellulose, a suspending agent, inwater). A group of nondiabetic mice from the same cohort that did notreceive STZ were also monitored. Blood samples were taken periodicallyfor determination of blood glucose concentrations, and body weights werealso recorded.

[1039] After several weeks of treatment, blood glucose concentrations inmice treated with oral Compound AH began to decrease toward baseline,whereas blood glucose in the vehicle-treated control animals continuedto rise. Body weights and blood glucose, triglyceride and cholesterolconcentrations 14 weeks after the beginning of drug treatment are shownin Table 1. TABLE 1 Serum chemistries and body weights in streptozotocindiabetic mice treated with oral Compound AH for 14 weeks GlucoseTriglycerides Cholesterol Body Group mg/dL mg/dL mg/dL Weight (g)Nondiabetic + 138 ± 6  88 ± 9  88 ± 6   21 + 0.6 Vehicle Diabetic + 615± 46 154 ± 16 133 ± 6 17.5 + 1.0 Vehicle Diabetic + 207 ± 12  62 ± 7* 82 ± 2* 21.7 + 0.8* Compound AH

[1040] Oral Compound AH treatment resulted in significant ameliorationof metabolic abnormalities associated with insulin-dependent diabetes.

Example B Oral Compound AH Improves Survival of Mice with LethalInsulin-Dependent Diabetes

[1041] Female Balb/C mice (14 weeks old) were treated with a single doseof streptozotocin (175 mg/kg i.p.) to induce severe insulin-dependentdiabetes. Seven days later, mice were divided into three treatmentgroups: Compound AH, pioglitazone, and vehicle. Mice were treated dailyvia oral gavage, and survival was monitored over time. TABLE 2 Survivalat 12 weeks Groups Survivors Vehicle 0/5 Pioglitazone 2/5 30 mg/kg/dayCompound AH 4/5 250 mg/kg/day

[1042] All of the diabetic animals treated with oral vehicle died ofsevere, uncontrolled diabetes. Two of five animals treated withpioglitazone, an antidiabetic insulin sensitizer used to treat humanswith noninsulin-dependent diabetes, were alive at 12 weeks, but had lost15-20% of their body weight. Four of the five animals treated with oralCompound AH were alive at 12 weeks, and their body weights recovered andwere maintained in the normal range.

Example C Oral Compound AA Reduces Mortality in Severe Insulin-DependentDiabetes

[1043] Female balb/C mice (19 wks of age at start of experiment) werechallenged with multiple high doses of STZ (75 mg/kg i.p. on 5consecutive days). Animals were then divided in two groups (20mice/group) matched for severity of diabetes. Four days after the lastdose of STZ, treatments were initiated. One group received Vehicle (0.4ml of 0.75% HPMC, p.o.), and the other group received oral COMPOUND AA(30 mg/kg/day). After three weeks of daily treatment, cumulativemortality in the Vehicle Control group was {fraction (19/20)} mice. Incontrast, only {fraction (5/20)} of the COMPOUND AA mice died duringthis time.

Example D Compound AH Reduces the Incidence of Spontaneous Diabetes andMortality in NOD Mice

[1044] A substantial proportion of NOD (“non-obese diabetic”) micedevelop insulin-dependent diabetes as a consequence of spontaneousautoimmune destruction of pancreatic islet cells.

[1045] Two groups of 20 NOD mice (6 weeks old) were treated daily witheither oral Vehicle (0.4 ml of 0.75% hydroxypropyl methylcellulose inwater; HPMC) or Compound AH (200 mg/kg/day) suspended in HPMC. Theincidence of mortality due to spontaneous development of severeinsulin-dependent diabetes was monitored over a period of seven months.At the end of this time, {fraction (13/20)} mice treated with vehiclehad died of uncontrolled diabetes, whereas only {fraction (5/20)} micetreated with Compound AH had died.

Example E Compound AW Reduces Hyperglycemia and Hyperlipidemia, andAmeliorates Fatty Liver Disease in ob/ob Obese Diabetic Mice

[1046] Ob/ob mice have a defect in the gene for leptin, a proteininvolved in appetite regulation and energy metabolism, and arehyperphagic, obese, and insulin resistant. They develop hyperglycemiaand fatty liver.

[1047] Male lean (ob/+ heterozygote) and obese (ob/ob homozygote)C57BL/6 mice approximately 8 weeks of age were obtained from JacksonLabs (Bar Harbor, Me.) and randomly assigned into groups of 5 animalssuch that body weights and blood glucose concentrations were similarbetween groups. All animals were maintained under the control oftemperature (23 C), relative humidity (50±5%) and light (7:00-19:00),and allowed free access to water and laboratory chow (Formulab Diet5008, Quality Lab Products, Elkridge, Md.). Blood glucose was routinelydetermined with glucose test strips and a Glucometer Elite XL device(Bayer Corporation). At selected time points, blood samples (˜1100microliters) were obtained with a heparinized capillary tube via theretro-orbital sinus for serum chemistry analysis. Serum chemistry(glucose, triglycerides, cholesterol, BUN, creatinine, AST, ALT, SDH,CPK and free fatty acids) analyses were performed on a Hitachi 717Analyzer, and plasma insulin and pancreatic insulin were measured by anelectrochemiluminescent immunoassay (Origen Analyzer, Igen, Inc.,Gaithersburg, Md.).

[1048] Groups of ob/ob mice were divided into treatment cohorts asindicated below, and given daily oral doses of Compound AW (10, 30, 100,150 or 300 mg), rosiglitazone (1, 3, 10 or 30 mg), or pioglitazone (30or 100 mg). The latter two compounds are insulin-sensitizing drugs usedin the treatment of human patients with non-insulin dependent diabetesmellitus, and are used as comparators for efficacy and safety ofcompounds of the invention. The dose ranges of compounds in thisexperiment were chosen to include both suboptimal and potentiallysupraoptimal doses.

[1049] Compound AW produced reduction in blood glucose comparable tothat achieved with pioglitazone and rosiglitazone, as shown in Table 3.At doses of 100 to 300 mg/kg/day, Compound AW reduced serumtriglycerides and fatty acids better than did either rosiglitazone orpioglitazone at their optimum antihyperglycemic doses. TABLE 3 Effect ofCompound AW, pioglitazone (PG) and rosiglitazone (RSG) on serum glucose,triglycerides, and free fatty acids in ob/ob mice Free Fatty Glucose ±Triglycerides ± Acids ± SEM Group SEM mg/dL SEM mg/dL micromoles/L ob/+ 268.6 ± 12.9  111.6 ± 12.0   2216 ± 197.4 ob/ob  384.2 ± 53.8  106.6 ±2.909   3399 ± 345.6 AW-10  369.6 ± 62.5  115.6 ± 7.8  3697.4 ± 357.8AW-30  280.2 ± 46.7  96.4 ± 7.3  2552.2 ± 334.7 AW-100   286 ± 47.1 66.2 ± 5.9   1476 ± 82.1 AW-150  188.6 ± 28.8  72.6 ± 5.6   1481 ±158.8 AW-300  128.4 ± 8.8  63.6 ± 3.4  1452.6 ± 111.1 PG-30  188.2 ±21.4  111.2 ± 7.5   2606 ± 139.2 PG-100  174.6 ± 11.5  95.2 ± 4.8 1983.4 ± 66.1 RSG-1 142.75 ± 8.8 109.75 ± 4.4 2090.75 ± 67.7 RSG-3 190.2 ± 12.7  107.8 ± 3.8  2317.6 ± 85.3 RSG-10  188.2 ± 21.4  111.2 ±7.5  2606.4 ± 139.2 RSG-30  174.6 ± 11.5  95.2 ± 4.8  1983.4 ± 66.1

[1050] Ob/ob mice develop chronic inflammatory fatty liver disease andare considered to be an animal model for nonalcoholic steatohepatitis(NASH), a condition which can lead toward progressive cirrhosis andliver dysfunction. In NASH, fat accumulation increases thesusceptibility of the liver to inflammatory injury. One characeristicsign of NASH in patients is, in the absence of viral infection oralcoholism, elevated levels in serum of enzymes that are released fromdamaged hepatocytes, e.g. alanine aminotransferase (ALT), aspartateaminotransferase (AST), and sorbitol dehydrogenase (SDH). These enzymesare elevated in ob/ob mice as a consequence of fatty liver and secondaryinflammation. In Table 4, ALT, AST, and SDH in serum samples from micetreated with Compound AW, pioglitazone, and rosiglitazone are shown, asare enzyme levels in serum from normal lean mice and from diabeticcontrol mice treated only with vehicle. ALT, AST and SDH aresignificantly elevated in obese diabetic ob/ob mice compared to leanmice. Compound AW treatment at doses ranging from 30 mg/kg/day to 300mg/kg/day resulted in a dose-dependent decrease in serum liver enzymes.In contrast, pioglitazone (30 and 100 mg/kg/day) and rosiglitazone (1 to30 mg/kg/day) induced an elevation in ALT and AST and did not changeSDH. The serum liver enzyme profiles correlated with liver histology.Vehicle-treated ob/ob obese diabetic mice had marked fat accumulation inthe liver in discrete intracellular droplets. Daily Compound AWtreatment for 4 weeks caused a marked reduction in liver fat droplets,whereas neither pioglitazone nor rosiglitazone reduced the size ordensity of fat droplets in the hepatocytes. TABLE 4 Effect of CompoundAW, pioglitazone and rosiglitazone on serum enzyme indicators of liverinjury ALT (U/L) ± AST (U/L) ± SDH (U/L) ± Group SEM SEM SEM Lean 106.4± 16.3  25.6 ± 2.7  23.2 ± 4.5 Diabetic 447.2 ± 63.4  645.6 ± 104.8745.8 ± 102.4 2022-10 483.8 ± 81.9  653.4 ± 104.8 626.8 ± 93.8 AW-30320.2 ± 46.2  399.6 ± 74.4 333.0 ± 66.9 AW-100 202.8 ± 38.0  143.8 ±30.4 121.2 ± 14.1 AW-150 149.2 ± 15.6  185.8 ± 26.0 166.2 ± 20.0 AW-300188.2 ± 10.3  335.4 ± 44.8 207.0 ± 29.3 PG-30 713.6 ± 80.6   1024 ± 88.7782.0 ± 70.6 PG-100 646.0 ± 56.1  901.0 ± 49.3 603.0 ± 27.3 RSG-1 668.8± 42.9  798.0 ± 73.8 644.5 ± 51.6 RSG-3 716.6 ± 56.6  853.8 ± 43.8 615.4± 38.6 RSG-10 713.6 ± 80.5 1024.0 ± 88.7 782.0 ± 70.6 RSG-30 646.0 ±56.1  901.2 ± 49.3 603.0 ± 27.3

[1051] The ob/ob Mice gained body weight during the four week treatmentperiod. As is shown in Table 5, pioglitazone and rosiglitazoneexacerbated weight gain relative to vehicle-treated mice; whereasCompound AW induced a dose-dependent attenuation of weight gain. TABLE 5Effect of Compound AW, Pioglitazone and Rosiglitazone on body weightgain of ob/ob mice Groups Mean body weight gain (grams) HPMC (Vehicle)+7.4 AW-3 mg/kg/day +7.3 AW-10 mg/kg/day +6.7 AW-30 mg/kg/day +6.4AW-100 mg/kg/day +3.4 AW-150 mg/kg/day +4.6 AW-300 mg/kg/day −0.7 PG-30mg/kg/day +10.0 PG-100 mg/kg/day +13.6 RSG-1 mg/kg/day +8.2 RSG-3mg/kg/day +8.5 RSG-10 mg/kg/day +11.0 RSG-30 mg/kg/day +12.0

Example F Acute Hypoglycemic Effects of Compounds of the Invention inDiabetic Mice: Experiment 1

[1052] Compounds of the invention display acute antihyperglycemicactivity in animals with non insulin-dependent diabetes.

[1053] Male ob/ob diabetic mice were randomized into groups of fiveanimals each. Body weights were 50-55 g and blood glucose wasapproximately 300 mg/dL in the fed state. A single oral dose of a testsubstance suspended in 0.5% carboxymethylcellulose vehicle wasadministered by gavage. Blood glucose was measured in blood dropletsobtained by nicking a tail vein with a razor using glucometer teststrips and a Glucometer Elite XL device (Bayer) at 0, 0.5, 2, 4, 6 and18 hours after the initial dosing. A 10% reduction in blood glucoseversus oral vehicle is considered a positive screening result. Bloodglucose reductions were generally maximal at 6 hours after drugadministration. TABLE 6 Acute hypoglycemic effect of compounds of theinvention in ob/ob obese diabetic mice Blood Glucose % Reduction vsTreatment Group After 6 hours Control Vehicle 297 ± 35    0.0 ± 11.8Compound AA 242 ± 25 −18.5 ± 8.4 Compound AB 181 ± 19 −39.1 ± 6.4Compound AF 314 ± 32 −24.6 ± 7.7 * Compound AG 222 ± 23 −25.3 ± 7.7Compound AH 223 ± 11 −24.9 ± 3.7 Compound AI 255 ± 9 −14.1 ± 3.0Compound AJ 190 ± 14 −36.0 ± 4.7 Compound AK 210 ± 10 −29.3 ± 3.4Compound AL 168 ± 13 −43.4 ± 4.4

Example G Acute Hypoglycemic Effects of Compounds of the Invention inDiabetic Mice: Expt 2

[1054] Compounds of the invention display acute antihyperglycemicactivity in animals with noninsulin-dependent diabetes.

[1055] Male ob/ob mice (50-55 grams; blood glucose ˜300 mg/dL) weredivided into groups of five animals each, and given a single oral doseof test drug (250 mg/kg) suspended in 0.5% carboxymethylcellulosevehicle; a control group received oral vehicle alone.

[1056] Six hours after oral administration of test drugs or vehicle(control), blood samples were obtained from a tail vein and glucosecontent was determined with a glucometer. TABLE 7 Acute hypoglycemiceffect of compounds of the invention in ob/ob obese diabetic mice BloodGlucose after 6 hours % Reduction vs Treatment Group 305 ± 20 ControlVehicle Control mg/dL    0.0 ± 5.0 Compound AN 152 ± 11 −50.2 ± 4.5%Compound AQ 220 ± 17 −27.9 ± 4.2% Compound AR 179 ± 14 −41.3 ± 4.2%Compound AS 167 ± 28 −45.2 ± 2.0% Compound AT 198 ± 28 −35.1 ± 2.3%Compound AU 224 ± 26 −26.6 ± 2.8% Compound AV 207 ± 23 −32.1 ± 3.0%Compound AW 143 ± 15 −53.1 ± 3.1% Compound AX 165 ± 23 −45.9 ± 2.4%Compound AY 185 ± 21 −39.3 ± 2.9% Compound AZ 186 ± 10 −39.0 ± 6.1%

[1057] Oral treatment with compounds of the invention elicits an acuteantihyperglycemic effect in obese diabetic mice.

Example H Antidiabetic Effects of Compounds of the Invention in db/dbMice

[1058] Db/db mice have a defect in leptin signaling, leading tohyperphagia, obesity and diabetes. Moreover, unlike ob/ob mice whichhave relatively robust islets, their insulin-producing pancreatic isletcells undergo failure during chronic hyperglycemia, so that theytransition from hyperinsulinemia (associated with peripheral insulinresistance) to hypoinsulinemic diabetes.

[1059] Male db/db mice were given daily oral treatments with vehicle(0.75% hydroxypropylmethylcellulose) or antidiabetic compounds asindicated below. Blood samples were obtained via the retro-orbital sinusfor serum chemistry analysis, or via the tail vein for glucosemeasurement with a test strip and glucometer.

[1060] After four weeks of daily oral dosing, Compound AW and CompoundBH elicited a significant reduction in blood glucose. While pioglitazonedid initially reduce blood glucose over the first 3 weeks, its activityhad largely failed at the 4 week time point and thereafter. The dose ofpioglitazone used in this experiment was reported in the literature tobe a maximally-effective dose for treatment of db/db mice (Shimaya etal. (2000), Metabolism 49:411-7). TABLE 8 Glucose Glucose Groups mg/dL(% of Control) Vehicle (Control) 562 ± 24 100 ± 4 Compound AW - 150 313± 34 *  56 ± 6 * mg/kg Compound BH - 150 mg/kg 229 ± 49 *  41 ± 9 *Pioglitazone - 100 mg/kg 558 ± 28  99 ± 5

[1061] In a second experiment in db/db mice, antidiabetic activity ofCompound BI was compared with that of rosiglitazone. After 8 weeks oftreatment, blood glucose and triglycerides were significantly lower inanimals treated with either Compound BI or rosiglitazone, compared tovehicle-treated controls. The rosiglitazone dose used in this study wasreported in published literature as the optimum dose for late stagedb/db mice (Lenhard et al., (1999) Diabetologia 42:545-54). Groupsconsisted of 6-8 mice each. TABLE 9 Glucose Triglycerides Groups (mg/dL)(mg/dL) Vehicle (Control) 686 ± 47 147 ± 13 Rosiglitazone-20 mg/kg 343 ±38 *  89 ± 16 * Compound BI-150 mg/kg 254 ± 30 *  99 ± 8 *

Example I Antidiabetic Effects of Compounds of the Invention in db/dbMice

[1062] db/db mice have a defect in leptin signaling, leading tohyperphagia, obesity and diabetes. Moreover, unlike ob/ob mice on aC57BL/6J background, db/db mice on a C57BL/KS background undergo failureof their insulin-producing pancreatic islet β cells, resulting inprogression from hyperinsulinemia (associated with peripheral insulinresistance) to hypoinsulinemic diabetes.

[1063] Male obese (db/db homozygote) C57BL/Ksola mice approximately 8weeks of age, were obtained from Jackson Labs (Bar Harbor, Me.) andrandomly assigned into groups of 5-7 animals such that the body weights(50-55 g) and serum glucose levels (≧300 mg/dl in fed state) weresimilar between groups; male lean (db/+ heterozygote) mice served ascohort controls. A minimum of 7 days was allowed for adaptation afterarrival. All animals were maintained under controlled temperature (23°C.), relative humidity (50±5%) and light (7:00-19:00), and allowed freeaccess to standard chow (Formulab Diet 5008, Quality Lab Products,Elkridge, Md.) and water.

[1064] Treatment cohorts were given daily oral doses of (1%hydroxypropylmethylcellulose), Compounds BI, BO, BP, BQ or BR for 2weeks. At the end of the treatment period 100 μl of venous blood waswithdrawn in a heparinized capillary tube from the retro-orbital sinusof db/db mice for serum chemistry analysis.

[1065] Effects of compounds of the invention on nonfasting blood glucoseare shown in Table 10; effects on serum triglycerides and free fattyacids are shown in Table 11. TABLE 10 The effects of Compounds BI, BO,BP, BQ or BR on blood glucose in the db/db mouse model Glucose GlucoseGroups mg/dL (% of Control) Vehicle (Control) 632 ± 19 100 ± 3 BI-150mg/kg 279 ± 35 *  44 ± 6 * BI-100 mg/kg 423 ± 53 *  67 ± 8 * BO-100mg/kg 586 ± 58  93 ± 9 BP-100 mg/kg 629 ± 86  99 ± 14 BQ-100 mg/kg 473 ±49 *  75 ± 7 * BR-82 mg/kg 703 ± 64 111 ± 10

[1066] TABLE 11 Effect of Compounds BI, BO, BP, BQ or BR on serumglucose, triglycerides, and free fatty acids in db/db mice Triglycerides± Free Fatty Group SEM (mg/dL) Acids ± SEM (μM) Lean 142.4 ± 6.3 2577.6± 80.8 Diabetic 444.3 ± 57.3 4044.9 ± 158.5 BI-150 103.6 ± 8.3 2234.0 ±162.6 BI-100 134.0 ± 13.1 2999.9 ± 98.7 BO-100 261.1 ± 24.3 3766.3 ±234.5 BP-100 302.1 ± 28.1 3772.6 ± 182.5 BQ-100 131.6 ± 20.7 2825.9 ±110.9 BR-82 253.0 ± 32.0 3653.4 ± 207.5

Example J Antidiabetic Effects of Compounds of the Invention in db/dbMice

[1067] db/db mice have a defect in leptin signaling, leading tohyperphagia, obesity and diabetes. Moreover, unlike ob/ob mice on aC57BL/6J background, db/db mice on a C57BL/KS background undergo failureof their insulin-producing pancreatic islet cells, resulting inprogression from hyperinsulinemia (associated with peripheral insulinresistance) to hypoinsulinemic diabetes.

[1068] Male obese (db/db homozygote) C57BL/Ksola mice approximately 8weeks of age, were obtained from Jackson Labs (Bar Harbor, Me.) andrandomly assigned into groups of 5-7 animals such that the body weights(50-55 g) and serum glucose levels (≧300 mg/dl in fed state) weresimilar between groups; male lean (db/+ heterozygote) mice served ascohort controls. A minimum of 7 days was allowed for adaptation afterarrival. All animals were maintained under controlled temperature (23°C.), relative humidity (50±5%) and light (7:00-19:00), and allowed freeaccess to standard chow (Formulab Diet 5008, Quality Lab Products,Elkridge, Md.) and water.

[1069] Treatment cohorts were given daily oral doses of Vehicle (1%hydroxypropylmethylcellulose), Compounds BI, BS, BT, BU, BV orFenofibrate for 2 weeks. At the end of the treatment period 100 μl ofvenous blood was withdrawn in a heparinized capillary tube from theretro-orbital sinus of db/db mice for serum chemistry analysis.

[1070] Effects of compounds of the invention on nonfasting blood glucoseare shown in Table 12; effects on serum triglycerides and free fattyacids are shown in Table 13. TABLE 12 The effects of compounds BI, BS,BT, BU, BV and fenofibrate in db/db mice Glucose Groups Glucose mg/dL (%of Control) Vehicle (Control) 692.5 ± 55.4 100 ± 8 BI - 100 mg/kg 347.0± 43.1*  50 ± 6* BS- 93 mg/kg 372.0 ± 53.8*  54 ± 8* BT - 107 mg/kg684.3 ± 63.6  99 ± 9 BU - 128 mg/kg 533.3 ± 46.7  77 ± 7 BV - 115 mg/kg789.5 ± 38.9 114 ± 6 Fenofibrate - 113 mg/kg 563.2 ± 49.0  81 ± 7

[1071] TABLE 13 Effect of compounds BI, BS, BT, BU, BV and Fenofibrateon serum triglycerides and free fatty acids in db/db mice Triglycerides± Free Fatty Group SEM (mg/dL) Acids ± SEM (μM) Lean 114.2 ± 8.7 2315.8± 238.3 Vehicle 232.8 ± 20.7 3511.8 ± 257.6 BI  77.8 ± 5.3 1997.2 ±196.4 BS 132.0 ± 15.2 2867.4 ± 267.7 BT 211.5 ± 21.5 3897.7 ± 291.3 BU172.5 ± 9.9 3587.0 ± 156.3 BV 153.2 ± 14.2 3373.8 ± 233.6 Fenofibrate109.3 ± 9.1 3318.5 ± 208.7

Example K Attenuation of Cataractogenesis of Compounds of the Inventionin Zucker Diabetic Fatty (ZDF) Rats

[1072] Cataracts are one of the leading causes of progressive visiondecline and blindness associated with ageing and diabetes, and theZucker diabetic fatty (ZDF) model has many similarities with humancataractogenesis, including biochemical changes and oxidative stress inthe lens. These rats, however, undergo cataractogenesis typicallybetween 14-16 weeks of age.

[1073] Male ZDF rats and their aged-match Zucker lean (ZL) counterparts(fa/+ or +/+) were obtained from Genetic Models, Inc. (Indianapolis,Ind.) aged 12 weeks and acclimatized for 1 week prior to study. Allanimals were maintained under controlled temperature (23° C.), relativehumidity (50±5%) and light (7:00-19:00), and allowed free access tostandard chow (Formulab Diet 5008; Quality Lab Products, Elkridge, Md.)and tap water ad libitum. Treatment cohorts were given a daily oral doseof vehicle and 100 mg/kg of BI or BH for 10 weeks. Body weights andblood glucose were routinely determined (once a week, usually around10:00 A.M.) from tail bleeds with glucose test strips and a GlucometerElite XL device (Bayer Corporation). At the end of the treatment period100 μl of venous blood was collected (usually 10:00 A.M.) in aheparinized tube from the tail vein for serum chemistry analysis(Anilytics, Inc., Gaithersburg, Md.). Serum chemistry (glucose (GL),triglycerides (TG), aspartate aminotransferase (AST), alanineaminotransferase (ALT), sorbitol dehydrogenase (SDH), and free fattyacids (FFA)) analyses were performed on a Hitachi 717 Analyzer(Anilytics, Inc., Gaithersburg, Md.). Plasma insulin was measured by anelectrochemiluminescent immunoassay, ECL (Origen Analyzer, Igen, Inc.,Gaithersburg, Md.). The animals were sacrificed and tissues and/ororgans (lens and liver) were extirpated, weighed (wet weight) andprocessed for biochemical analyses. Malondialdehyde (MDA), a majorproduct of lipid peroxidation was assayed in lenses according to Ohkawaet al (1979), Analytical Biochem 95, 351-358).

[1074] Table 14 shows the incidence of visible cataracts in the eyes ofthe ZDF rats. Table 15 indicates additional quantitative indices ofcataractogenesis in the same animals. TABLE 14 Attenuation ofcataractogenesis by Compounds BH and BI in ZDF rats. Cataract Formation% Protection Animal Groups N Left Eye Right Eye Left Eye Right EyeVehicle-Control 6 6/6 6/6  0  0 BI 6 3/6 1/6 50 83 BH 6 4/6 5/6 33 17Lean 4 0/4 0/4 N/A N/A

[1075] TABLE 15 Attenuation of cataractogenesis by BH and BI in ZDFrats. Lenticular Weight (mg) Size (mm) MDA Right nmol/g Groups Left LensRight Lens Left Lens Lens lens LEAN 51.2 ± 3.5  59.0 ± 0.4  3.8 ± 0.2 3.9 ± 0.1  0.4 ± 0.0  Vehicle 15.1 ± 1.4  16.8 ± 1.7  1.9 ± 0.1  2.0 ±0.2  2.4 ± 0.2  BI 38.1 ± 7.3** 54.9 ± 1.2* 3.4 ± 0.2* 3.8 ± 0.1* 0.8 ±0.1‡ BH 27.0 ± 7.2  20.0 ± 6.6  2.5 ± 0.3  2.1 ± 0.4  1.9 ± 0.2 

Example L Oral BI and BL Lower Circulating Triglycerides, Free FattyAcids, Insulin and Leptin in High Fat-Fed C57B1/6J Mice

[1076] The high fat-fed mouse is a model for the hypertriglyceridemiaand high circulating fatty acid levels, and the insulin and leptinresistance that are found in people at risk for and with obesity,diabetes, cardiovascular disease and other disorders. Male C57B1/6Jmice, approximately 8 weeks of age, were randomly assigned into groupsof 6 animals. They were maintained under controlled temperature (23°C.), relative humidity (50±5%) and light (7:00-19:00), and allowed freeaccess to food and water ad libitum. Mice were fed a high-fat diet (dietnumber D12451, containing 45% of calories as fat (Research Diets, NewBrunswick, N.J.)) for 6 weeks. After the 6 weeks, groups of micereceived either vehicle (hydroxymethylcellulose), BI, BL, Wy14,643 orrosiglitazone by oral gavage at the indicated doses for an additional 4weeks while continuing on the high-fat diet. Plasma chemistries(Anilytics, Inc., Gaithersburg, Md.) were assayed after 2 weeks of drugtreatments. Plasma serum insulin (FIG. 1) and leptin (FIG. 2) weremeasured by an electrochemiluminescent immunoassay (Origen Analyzer,Igen, Inc., Gaithersburg, Md.) after 4 weeks of drug treatments.

[1077] BI and BL were effective at lowering serum triglycerides and freefatty acids as well as insulin and leptin serum levels. Serum valuesfrom mice from the same cohort (“lean controls”) that were maintained onregular lab chow (Formulab Diet 5008, Quality Lab Products, Elkridge,Md.) are shown for comparison. TABLE 16 Triglycerides Free Fatty (mg/dL)Acids (umol/L) Vehicle   135 ± 40.1   1686 ± 359.3 BI (10 mg/kg)  68.8 ±5.7   1227 ± 193.7 BI (30 mg/kg)  66.5 ± 14.7   1292 ± 231.4 BI (100mg/kg)  37.4 ± 8.3  992.8 ± 172.1 BL (10 mg/kg)   80 ± 12.2 1571.8 ±100.9 BL (30 mg/kg)  66.4 ± 13.7 1413.2 ± 228.7 BL (100 mg/kg)   41 ±5.6 1133.5 ± 132.7 Rosiglitazone (1 mg/kg)  76.6 ± 16.5   1537 ± 256.3Rosiglitazone (3 mg/kg) 103.2 ± 10.8 1833.2 ± 169.8 Rosiglitazone (10mg/kg) 129.5 ± 48.7 1810.3 ± 595 Rosiglitazone (100 mg/kg)   88 ± 7.21568.5 ± 197 Wy14643 (10 mg/kg)  70.6 ± 10.8 1512.2 ± 172.9 Wy14643 (30mg/kg)   88 ± 12.5   1676 ± 237 Wy14643 (100 mg/kg)  88.4 ± 18.8 1839.8± 154.8 Rosi (3 mg/kg) +  54.3 ± 10.5 1649.7 ± 260.5 Wy14643 (100 mg/kg)

Example M Oral BI Lower Circulating Triglycerides, Free Fatty Acids,Insulin and Leptin in High Fat-Fed Sprague Dawley Rats

[1078] The high fat-fed rat is a model for insulin and leptinresistance. Sprague-Dawley rats have an intact leptin system and respondto a high fat diet with hyperinsulinemia due to a downregulation of thenormal insulin response in peripheral tissues such as liver, adiposetissue and muscle

[1079] Male Sprague-Dawley rats, approximately 17 weeks of age, wereobtained from Jackson Labs (Bar Harbor, Me.) and randomly assigned intogroups of 5-7 animals; the body weights were similar between groups. Allanimals were maintained in a temperature-controlled (25° C.) facilitywith a strict 12 h light/dark cycle and were given free access to waterand food. Rats were fed a high-fat diet (diet number D12451 (containing45% of calories as fat), Research Diets, New Brunswick, N.J.) for onemonth prior to drug treatment.

[1080] Groups of 6 Sprague-Dawley rats were treated with a single dailydose of vehicle (hydroxymethylcellulose), BI (10, 30 and 100 mg/kg), orrosiglitazone (3 mg/kg) for 6 weeks while maintaining the high-fat diet.At the indicated time points, blood samples (˜100 μl) were obtained viathe tail vein for serum chemistry analysis.

[1081] BI (30 mg/kg) reduced serum insulin, triglycerides; BI at alldoses reduced free fatty acids. TABLE 17 Effect of BI and rosiglitazoneon serum glucose, insulin, triglycerides and free fatty acids inhigh-fat fed Sprague-Dawley rats Free Fatty Glucose InsulinTriglycerides Acids Group (mg/dL) (ng/ml) (mg/dL) (μMol/L) Lean 123.8 ±7.0 0.72 ± 0.1 179.0 ± 72.3 743.5 ± 57.4 Vehicle 122.3 ± 5.9 1.78 ± 0.3200.7 ± 39.2 942.5 ± 181.0 BI-10 117.3 ± 8.8 2.18 ± 0.9 183.7 ± 58.4923.7 ± 161.3 BI-30 127.3 ± 22.2 1.46 ± 0.2 129.3 ± 20.0 738.7 ± 50.0BI-100  19.3 ± 3.5 1.79 ± 0.2 171.7 ± 33.1 725.7 ± 87.5 RG-3 119.8 ± 5.41.57 ± 0.2 134.2 ± 15.2 758.8 ± 61.0

What is claimed is:
 1. A biologically active agent, wherein the agent isa compound of the formula:

wherein n is 1 or 2; t is 0 or 1; m is 0 and r is 1, or m is 1 and r is0; A is phenyl, unsubstituted or substituted by 1 or 2 groups selectedfrom: halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxyhaving 1 or 2 carbon atoms, and perfluoromethoxy; or cycloalkyl havingfrom 3 to 6 ring carbon atoms wherein the cycloalkyl is unsubstituted orone or two ring carbons are mono-substituted by methyl or ethyl; or a 5or 6 membered heteroaromatic ring having 1 or 2 ring heteroatomsselected from N, S and O and the heteroaromatic ring is covalently boundto the remainder of the compound of formula II by a ring carbon; Z is

R¹ is hydrogen or alkyl having from 1 to 7 carbon atoms; R⁴ is hydrogen;—NHCOOC(CH₃)₃; —NHCH₃; or —NHCH₂CH₃; or when R¹ is hydrogen, apharmaceutically acceptable salt of the compound.
 2. The agent of claim1, wherein A is cycloalkyl having from 3 to 6 ring carbon atoms whereinthe cycloalkyl is unsubstituted or one or both of the ring carbonsadjacent to the remainder of the compound of formula II aremono-substituted by methyl or ethyl.
 3. The agent of claim 1, wherein Ais phenyl, unsubstituted or substituted by 1 or 2 groups selected from:fluoro, alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxy having1 or 2 carbon atoms, and perfluoromethoxy.
 4. The biologically activeagent of claim 3, wherein the agent is a compound of the formula:

wherein m is 0 or 1; r is 0 or 1; Z is

R¹ is hydrogen or alkyl having from 1 to 7 carbon atoms; R⁴ is hydrogen;—NHCOOC(CH₃)₃; —NHCH₃; or —NHCH₂CH₃; R³ is hydrogen or halo; or when R¹is hydrogen, a pharmaceutically acceptable salt of the compound.
 5. Theagent of claim 4, wherein R¹ is hydrogen or ethyl.
 6. The agent of claim5, wherein the compound is3-[(4-(2-fluorobenzyloxy)phenyl)methylthio]propionic acid.
 7. The agentof claim 5, wherein the compound is3-[(4-(2,6-difluorobenzyloxy)phenyl)methylthio]propionic acid.
 8. Theagent of claim 5, wherein the compound is(2RS)2-(N-Boc)-3-[2-(4-(2,6-difluorobenzyloxy)phenyl)-2-oxoethyl]thiopropionicacid.
 9. A biologically active agent, wherein the agent is a compound ofthe formula:

wherein n is 1 or 2; R¹ is hydrogen or alkyl having from 1 to 7 carbonatoms; R¹⁴ is hydroxy or hydrogen; and A is phenyl, unsubstituted orsubstituted by 1 or 2 groups selected from halo, alkyl having 1 or 2carbon atoms, perfluoromethyl, alkoxy having 1 or 2 carbon atoms, andperfluoromethoxy; or cycloalkyl having from 3 to 6 ring carbon atomswherein the cycloalkyl is unsubstituted or one or two ring carbons areindependently mono-substituted by methyl or ethyl; or a 5 or 6 memberedheteroaromatic ring having 1 or 2 ring heteroatoms selected from N, Sand O and the heteroaromatic ring is covalently bound to the remainderof the compound of formula V′ by a ring carbon; or a pharmaceuticallyacceptable salt of the compound.
 10. The biologically active agent ofclaim 9, wherein the agent is a compound of the formula:

wherein n is 1 or 2; R¹ is hydrogen or alkyl having from 1 to 7 carbonatoms; A is phenyl, unsubstituted or substituted by 1 or 2 groupsselected from halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl,alkoxy having 1 or 2 carbon atoms, and perfluoromethoxy; or cycloalkylhaving from 3 to 6 ring carbon atoms wherein the cycloalkyl isunsubstituted or one or two ring carbons are independentlymono-substituted by methyl or ethyl; or a 5 or 6 membered heteroaromaticring having 1 or 2 ring heteroatoms selected from N, S and O and theheteroaromatic ring is covalently bound to the remainder of the compoundof formula V by a ring carbon; or a pharmaceutically acceptable salt ofthe compound.
 11. The biologically active agent of claim 10, wherein theagent is a compound of the formula:

wherein n is 1 or 2; R¹ is hydrogen or alkyl having from 1 to 7 carbonatoms; R² and R³ are each independently selected from hydrogen, halo,alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxy having 1 or 2carbon atoms, and perfluoromethoxy; or a pharmaceutically acceptablesalt of the compound.
 12. The agent of claim 11, wherein R¹ is hydrogenor ethyl.
 13. The agent of claim 12, wherein the compound is ethyl2-hydroxy-4-oxo-4-(4-(2,6-difluorobenzyloxy)phenyl) but-2-enoate. 14.The agent of claim 9, wherein the compound is4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxo-2-butenoic acid.
 15. Abiologically active agent, wherein the agent is a compound of theformula:

wherein n is 1 or 2; R¹ is hydrogen or alkyl having from 1 to 3 carbonatoms; and A is phenyl, unsubstituted or substituted by 1 or 2 groupsselected from halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl,alkoxy having 1 or 2 carbon atoms, and perfluoromethoxy; or cycloalkylhaving from 3 to 6 ring carbon atoms wherein the cycloalkyl isunsubstituted or one or two ring carbons are independentlymono-substituted by methyl or ethyl; or a 5 or 6 membered heteroaromaticring having 1 or 2 ring heteroatoms selected from N, S and O and theheteroaromatic ring is covalently bound to the remainder of the compoundof formula XCI by a ring carbon; or a pharmaceutically acceptable saltof the compound.
 16. The agent of claim 15, wherein the compound is4-(3-(2,6-Dimethylbenzyloxy)phenyl)-3-butenoic acid.
 17. A biologicallyactive agent, wherein the agent is a compound of the formula:

wherein n is 1 or 2; R¹ is hydrogen or alkyl having from 1 to 3 carbonatoms; and A is phenyl, unsubstituted or substituted by 1 or 2 groupsselected from halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl,alkoxy having 1 or 2 carbon atoms, and perfluoromethoxy; or cycloalkylhaving from 3 to 6 ring carbon atoms wherein the cycloalkyl isunsubstituted or one or two ring carbons are independentlymono-substituted by methyl or ethyl; or a 5 or 6 membered heteroaromaticring having 1 or 2 ring heteroatoms selected from N, S and O and theheteroaromatic ring is covalently bound to the remainder of the compoundof formula CXVI by a ring carbon; or a pharmaceutically acceptable saltof the compound.
 18. The agent of claim 17, wherein the compound is4-(3-(2,6-Dimethylbenzyloxy)phenyl)butyric acid.
 19. A biologicallyactive agent, wherein the agent is a compound of the formula:

wherein n is 0, 1 or 2; R¹ is hydrogen or alkyl having from 1 to 3carbon atoms; R¹⁵ is hydrogen or alkyl having from 1 to 3 carbon atoms;R⁹ is hydrogen, halo, hydroxy, or alkoxy having from 1 to 3 carbonatoms; A is phenyl, unsubstituted or substituted by 1 or 2 groupsselected from halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl,alkoxy having 1 or 2 carbon atoms, and perfluoromethoxy; or cycloalkylhaving from 3 to 6 ring carbon atoms wherein the cycloalkyl isunsubstituted or one or two ring carbons are independentlymono-substituted by methyl or ethyl; or a 5 or 6 membered heteroaromaticring having 1 or 2 ring heteroatoms selected from N, S and O and theheteroaromatic ring is covalently bound to the remainder of the compoundof formula I by a ring carbon; or a pharmaceutically acceptable salt ofthe compound.
 20. The agent of claim 19, wherein the compound is4-{3-[((4-Trifluoromethylbenzylamino)-carbonyl)-4-methoxy]phenyl}-4-oxobutyricacid.
 21. The agent of claim 19, wherein the compound is4-{3-[((2,6-Dimethyllbenzylamino)carbonyl)-4-methoxy]phenyl}-4-oxobutyricacid.